THE LIBRARY OF THE UNIVERSITY OF CALIFORNIA PRESENTED BY PROF. CHARLES A. KOFOID AND MRS. PRUDENCE W. KOFOID TEXTBOOK OF PHAEMACOLOG-T AND THEEAPEUTICS OR THE ACTION OF DRUGS IN HEALTH AND DISEASE BY ARTHUR R. CUSHNY, M.A., M.D., ABERD. PROFESSOR OF PHARMACOLOGY IN THE UNIVERSITY COLLEGE, LONDON, ENG. ; FORMERLY PRO- FESSOR OF MATERIA MEDICA AND THERAPEUTICS IN THE UNIVERSITY OF MICHIGAN; THOMPSON FELLOW IN THE UNIVERSITY OF ABERDEEN AND ASSISTANT IN THE PHARMACOLOGICAL INSTITUTE OF THE UNIVERSITY otf STRASSBURG. FOURTH EDITION, THOROUGHLY REVISED. ILLUSTRATED WITH FIFTY-TWO ENGRAVINGS LEA BROTHERS & CO. PHILADELPHIA AND NEW YORK Copyright, 1906, by LEA BROTHERS & CO. Authority to use for comment the Pharmacopoeia of the United States of America (Eighth Decennial Eevision), in this volume, has been granted by the Board of Trustees of the United States Pharmacopreial Convention ; which Board of Trustees is in no way responsible for the accuracy of any translations of the Official Weights and Measures, or for any statement as to strength of Official Preparations. K- R3 I <* 7 OSWALD SCHMIEDEBERG, MEISTER, YOM SCHULKK GEWIDMET. PREFACE TO THE FOURTH EDITION. THE revision of the United States Pharmacopoeia has necessitated the issue of a new edition of this text-book, and the opportunity has been taken to record such advances in the subjects of Pharmacology and Therapeutics as have been made in the last two years. In order to permit of this being done, and, in particular, to admit of references to the newer literature of the subject, some of the older bibliography has been curtailed. As a general rule, the new authors quoted have given references to their predecessors, but in some instances it may be necessary to refer to the earlier editions in order to complete the bibli- ography. The changes made in the text are too numerous to be detailed here, but perhaps attention may be called to the new features brought out by Embley and others in regard to the action of chloro- form and its dangers, and to the change in the views held as to the effects of wood -alcohol in man. The index of drugs, classified according to their therapeutic uses, has been retained in view of its manifest usefulness. I have to express again my appreciation of the kindness of many friends who have aided me by suggestions, and to record my indebted- ness to Dr. W. J. McNeal for reading the proofs of this edition. A. E. C. PREFACE TO THE FffiST EDITION. THE following pages were written to supply a want which I have felt keenly in teaching the subject of pharmacology to students who have completed the purely scientific branches of medicine and are be- ginning their clinical studies. My object has been to bridge over the hiatus which exists between the phenomena occurring in the normal organism and those which are elicited in the therapeutic use of drugs, to show how far the clinical effects of remedies may be explained by their action on the normal body, and how these may in turn be cor- related with physiological phenomena. It necessarily follows that the subject is treated from the experimental standpoint, and that the re- sults of the laboratory investigator are made the basis of almost every statement. Where these fail to elucidate the therapeutic effects or even to suggest a possible explanation, I have preferred to leave the question undiscussed rather than to call on such occult del ex machina as alterative or tonic actions. Two great difficulties present themselves at the outset to the writer on pharmacology who is not satisfied to take his statements at second hand, or to formulate explanations from his unaided inner conscious- ness ; these are the overwhelming literature on the subject, and the wide limits of the field of study. As regards the first, I have read, as far as was in my power, the original papers of importance, and in order to facilitate the work of others who may wish to follow this, the only satisfactory method of study, have appended a bibliography to each chapter. It was impossible within the limits of a textbook to make this complete, or even to enumerate more than a few of the works con- sulted, and I have accordingly selected those which appeared most important, and those which were furnished with the most complete bibliography. As regards the scope of the work, I have attempted to give the present standpoint of knowledge of such bodies as are of therapeutic or toxicological interest, and also of those which, possessing in themselves no immediate interest in practical medicine, have thrown important light on biological problems, and are accordingly likely to be referred to in scientific literature. 8 PREFACE. Unfortunately, a writer on this subject cannot as yet restrict his at- tention to these classes, but must refer at more or less length to many drugs which possess little interest either from a therapeutic or a scien- tific point of view. It is true that the more advanced teachers of medicine have very properly abbreviated their lists of remedies, until those generally employed may be enumerated in units where they were once counted in scores, but the student on going into practice meets numbers of drugs previously unknown to him, and not appreciating that these have already been tried and discarded by his teachers, is tempted to fall into the slough of unreasoning empiricism. There is still a tendency even among the educated to ascribe therapeutic virtues to every new weed and every new product of chemical industry, and the teacher of pharmacology must not only point out the good, but has the more ungrateful task of condemning the worthless. The period of constructive pharmacology has scarcely dawned ; at present its chief function is destructive and critical. In dealing with each drug, I have attempted to unify the whole ac- tion by using the most distinctive feature as a centre around which to group the less important symptoms. Where, as is often the case, there is a divergence of views among authorities, I have generally pre- sented only one side of the question, except in very important subjects. This dogmatic method has of course , its drawbacks, but is, I think, preferable to involving the student in a labyrinth of arguments and counter-arguments, the respective weight of which he is quite unable to estimate. The preparations enumerated are those included in the United States and the British Pharmacopoeias, and such others as seemed of sufficient importance. I have attempted to indicate by special type (small capi- tals) those that are more generally used. Some explanation may seem necessary for the introduction of the word " therapeutics " in the title, in view of the fact that pharmacology is stated in the introduction to embrace all that part of therapeutics which can be treated of apart from clinical lectures. This definition is not universally used, however, and it has been felt advisable to in- dicate more distinctly the scope of the work by adding the more familiar term. To those acquainted with the Grundriss der Arzndmittellehre of Schmiedeberg, it is unnecessary to state that this volume has been largely inspired by that classical work. Some chapters may in fact be regarded as merely expansions of those issued from the Strassburg laboratory, but this must necessarily be the case in any work which PREFACE. 9 pretends to treat the subject from the experimental standpoint. The use of such a model naturally exposes the writer to the criticism that he has fallen short of the original standard, especially when such divergences are made from it as occur in this work. But if I have departed from the letter in some respects, I hope that at least the spirit of the Grundriss has been preserved in these pages. . I must acknowl- edge my indebtedness for references to papers which might have otherwise escaped my notice to the following textbooks : Kobert's Lehrbuch der Intoxicationen, Lewin's Nebenwirkungen der Arzneimittel, Husemann's Pflanzenstoffe, Harnack's Arzneimittettehre, H. C. Wood's Therapeutics, its Principles and Practices and Stokvis' Leqons de Phar- macotherapie. Finally, I have much pleasure in acknowledging the assistance of my colleagues in the preparation of this work, particularly that of Profes- sor Huber, who furnished several of the illustrations. Dr. G. B. Wallace has put me under lasting obligations through the patience and care which he has bestowed on the tedious task of proof-correction, and I must thank Dr. W. Mogk also for his assistance in this part of the work. UNIVERSITY OF MICHIGAN, ANN ARROR, MICH., June, 1899. CONTENTS. PAGE. Introduction. 17 Mode of action of drugs, stimulation, depression, irritation . . 20 Elective affinity of drugs, protoplasm poisons .... 22 Remote, local and general action 23 Chemical composition and pharmacological action ... 24 Conditions modifying the effects of drugs ..... 25 Methods of administration ........ 30 Chemical characters of drugs 34 Pharmacopoeias and pharmacopceial preparations . ... 37 Classification of drugs , ,41 PAKT I. ORGANIC SUBSTANCES WHICH ARE CHARACTERIZED CHIEFLY BY THEIR LOCAL ACTION .... 45 1. Demulcents ........... 45 2. Emollients . . .49 3. Sugars and flavoring substances ....... 54 4. Simple bitters 55 5. Volatile oil series . . 61 Flavoring agents and carminatives. 66 Pepper group. 72 Malodorous volatile oils 73 Genito-urinary disinfectants 74 Uva ursi 77 6. Skin irritants and counter-irritation 78 Turpentine oil group 85 Mustard 88 Cantharidin series . 89 7. Vegetable purgatives 93 Purgative oils. . 97 Anthracene purgatives .99 Jalapin and colocynthin group 103 8. Vegetable astringents tannic acid group ..... 109 9. Anthelmintics 115 Male fern 116 Cusso 118 Granatum 119 Santonin 120 14 CONTENTS. PAGE; 22. Charcoal 578 23. Boracic acid and borax 578 24. Carbonic acid 580 25. Chlorine and bromine 582 26. Oxygen 585 27. Peroxide of hydrogen ......... 587 28. Phosphorus 591 29. Arsenic . . , 603 PAKT IY. THE HEAVY METALS 621 1. Antimony 629 2. Mercury 634 3. Iron 655 4. Lead 670 5. Copper 680 6. Zinc 683 7. Silver 686 8. Bismuth 692 Cerium 695 9. Aluminium and alum 695 10. Minor metals 698 Gold 698 Platinum 698 Chromium 699 Manganese ........... 700 PAKT V. FERMENTS, SECRETIONS AND TOXALBUMINS . . .705 1. Digestive ferments . ......... 705 Pepsin 705 Pancreatic ferments 706 Vegetable ferments 707 Diastase 707 2. Bile 708 3. Internal secretions . 710 Thyroid gland 711 Other internal secretions 718 4. Toxalbumins 720 5. Cod-liver oil 722 6. Phloridzin . . - .725 PART VI. MENSTRUA AND MECHANICAL REMEDIES . 727 A TEXT BOOK OF PHARMACOLOGY. INTRODUCTION. PHARMACOLOGY is the study of the changes induced in living organ- isms by the administration in a state of minute division of such un- organized substances as do not act merely as foods. Many of the best known of these substances are used to counteract the effects of disease, or to reinforce the tissues in their struggle to maintain their functions, when these are rendered abnormal. These substances are known 'as drugs, and the art of applying drugs in disease, is Therapeutics. Other substances are of little or no value in disease, but are of importance because they act as poisons, that is, cause dangerous or fatal symptoms in man or animals, when they are ingested in quantity. The practical study of the effects of these poisons in man the diagnosis and the treatment of poisoning, and the methods of detecting the poison is termed Toxicology. But the explanation of the symptoms induced by chemical substances, and their study, as apart from their practical ap- plications, belong to the field of pharmacology, which includes not only the effects of drugs and poisons, but those of any substance which induces changes in the living organism, whether those changes are of benefit to it, injurious, or quite indifferent. 1 The substances must, of course, conform to the requirements of the defini- tion. Thus, a needle introduced into the tissues induces effects which are outside the field of pharmacological investigation, because it is not in a state of minute division. But the iron of the needle may be reduced to a fine powder and induce changes in the body which are then the legitimate subject of research. Similarly the drug must be introduced from without, for many active agents are formed within the body, but their study belongs rather to the departments of physiology and pathology ; and the effects of organized bodies introduced from without are now studied under bacteriology. Phar- macology is really a department of biology, very closely related to the other sciences included by that term. Thus, as physiology is the study of the life of the normal organism, pharmacology is the study of the organism rendered abnormal by drugs, while in pathology the phenomena of life under disease are examined. All three subjects may be pursued without reference to the practical needs of medicine, and all three are closely interconnected and mutually dependent, for, in many instances, the normal condition of an organ can be recognized only by considering the results of its destruction by disease (pathology), or of its paralysis or stimulation by chemical agents 1 It is quite impossible to distinguish between drugs and poisons. Almost all reme- dies given in excess cause dangerous or fatal symptoms, while many poisons are valuable remedies in small doses. Some bodies may in fact be remedies, foods, or poisons accord- ing to the quantity ingested and the method of application. 2 17 18 INTRODUCTION. (pharmacology). Similarly, many of the features of disease are now rec- ognized to be due to the presence of unorganized poisons formed in and by the tissues, and it accordingly becomes difficult to accurately define the limits of pathology and pharmacology. Thus, the toxines formed by microbes resemble in their action some of the ordinary drugs or poisons, and might be considered along with these. But the study of these toxines is so closely bound up with that of the microbes from which they originate, that it has been thought better to leave them to be treated by special text-books on bac- teriology. For a similar reason the antitoxines, which play so prominent a role in modern therapeutics, may be excluded from treatises on pharmacol- ogy, for the present at any rate. Even when these limitations are accepted, pharmacology has an enormous field to cover, and one which has been only very partially ex- plored at the present day, in spite of the unremitting industry of many investigators. But a small part of the subject has been sufficiently developed to admit of text-book treatment, that namely, which is con- cerned with drugs used in therapeutics and with the commoner poisons. The slow advance of pharmacology is partly due to its position midway between the biological sciences and practical therapeutics, for while the biologist confounds it with clinical study, the clinician regards it as an experimental science. Its relation to biology has already been men- tioned and its relation to practical therapeutics is no less close, for the effects of drugs in disease are as much a part of pharmacology as is their action in the nonnal organism. The aim's of the pharmacologist and the clinician are not identical, however. The former seeks to solve the problem how the drug acts in a given case, while the primary object of the latter is to remedy the condition by any means in his power. Thus, in a case of heart weakness, the clinician prescribes some remedy which he has found of benefit in other similar cases, and regards only as of secondary interest the question which to the pharmacologist is the absorbing one, namely, whether the drug acts on the heart directly or through some other organ. Of course the results are of mutual ad- vantage, for the physician supplies the experimental investigator with new facts and with new fields of inquiry, while the latter may indicate more exactly the conditions in which the drug is likely to be of benefit in the future by defining the method in which it acts. It is, therefore, much to be regretted that differences of opinion so often arise between these two classes of observers, for these can only retard the progress of both the science and the practical art. Doubtless there are often faults on both sides. The scientist sometimes insists too strongly on induc- tions drawn from a limited number of animal experiments, and refuses to admit results which have been obtained in thousands of cases of dis- ease by competent observers. On the other hand, the therapeutist often lays too little weight on the general principles governing the interaction of the drug and the organism. Both often exceed the limits of their provinces, the scientist in refusing to admit effects of which he has per- force but a small experience, the clinician in attempting to refute de- ductions founded on experiments which he has no opportunity of per- forming. An example may render the relation of these allied subjects PHAEMA COLOG Y. 19 clearer, and one has been recently offered in the discussion regarding the effects of iron. This metal has been used for many years in a form of anaemia, and its curative properties are attested by many thousands of cases and by whole generations of practical physicians. A phar- macologist, therefore, exceeds his province when he expresses doubt regarding this clinical fact simply because he is unable to explain it, but he is within his rights in discussing the means by which iron acts as a remedy. The clinician, on the other hand, enters on a pharma- cological question when he attempts to determine whether iron acts by absorption or by its presence in the bowel, and must base his argu- ments on scientific experiment and not on his clinical experience of the curative effects of the metal. Fortunately for the progress of medicine and pharmacology, the scientific clinician is imbued with the desire to ascertain the methods in which drugs act as well as to cure disease, and thus unites clinical observation with pharmacological research. It is to be anticipated that the results of the practical physician and of the experimental investigator will come into more complete accord as more exact methods of clinical research are used by the former, and a wider laboratory experience is attained by the latter. But both methods are necessary to the complete knowledge of the action of a drug. Animal experiment cannot be dispensed with, for only thus can the action of drugs be ascertained in detail and expeditiously, and at the present time, when a new remedy appears almost every week, it is impossible to await the verdict of the clinics to separate the useful from the worthless, even if it were permissible to apply to the human subject drugs of unknown action and potency. Pharmacology is one of the most recent developments of medical and biological science. It is true that from the earliest times attempts have been made to explain the effects of drugs on the then prevailing theo- ries of pathology, but the objective study of the action of drugs on the organism has been a development of the nineteenth century, or it might almost be said, of the second half of it. During this period the same methods of research have been adopted as had earlier proved so fruitful in physiology and pathology, and with equally happy results. The study of drugs was termed Materia Medica up to this time, and com- prised an examination of their botanical and chemical properties along with some account of the diseases in which they had proved of value. This descriptive rather than experimental study has been continued under the name of Pharmacognosy, but is now pursued by pharmacists chiefly. Undoubtedly the student of medicine ought to know those characters of drugs which are of importance as modifying their action and application, but it is undesirable that his valuable time should be occupied in the detailed description of crude substances, which he may probably never have an opportunity of seeing in his future practice. Another subject which now occupies a much less prominent position in medical study than formerly, is Pharmacy, or the art of preparing drugs for therapeutic use. Some general knowledge of the methods used is no doubt indispensable to the educated physician, but the de- 20 INTRODUCTION. tails may be left to the pharmacist. Pharmacy will probably occupy a still more subordinate position in medical education as the tendency to include only one or two drugs in a prescription becomes more wide- spread. As long as a dozen or more components went to make one mixture, it was of importance to know their solubility and their inter- actions, but with the decay of the complex prescription the study of pharmacy by medical students has certainly become less imperative. MODE OF ACTION OF DRUGS. STIMULATION, DEPRESSION AND IRRITATION. A small number of drugs affect the organism only through their phy- sical properties, as when an inert oily body is applied to an abraded surface and promotes its healing by protecting it from irritation and from the evaporation of fluid, or when common salt absorbed into the blood changes its osmotic tension, and thus alters the distribution of fluids in the tissues. But the great majority of drugs act through their chemical affinity for certain forms of living matter. They probably form temporary combinations with some forms of protoplasm, and alter the function of all cells, which contain these forms. At least this is the only explana- tion of their affecting certain organs while others escape their influ- ence. To take an example, the cells of the spinal cord normally receive sensory impressions from the exterior and send out motor impulses. But under strychnine the motor impulses are much more violent than usual, and this may be expressed by saying that the combination of strychnine and cord protoplasm functions more powerfully than unal- tered cord protoplasm. The activity is changed, however, only in de- gree and not in kind ; the reflex movement may be more powerful or less powerful than normally, but it remains a reflex movement and can- not under any circumstances partake of the nature of a voluntary move- ment. In other words, the action of drugs is quantitative and not qualitative, the activity of living matter may be changed, but the form which the activity assumes is unchangeable. In recent years much attention has been paid to a series of natural phenomena occurring in the border-land between physics and chem- istry and the application of the results of " physical chemistry " to pharmacology has proved of great value already and promises to eluci- date in the future many problems which have hitherto been unap- proachable. Examples of such applications will be met in the Meyer- Overton theory of narcosis and in the chapters on salt action. The tendency of study in this direction is to reduce the class of reactions which have hitherto been ascribed to special chemical affinity between drugs and protoplasm and to attribute many of the changes induced by drugs to the physical structure of the living cell rather than to its chemical constitution. Drugs which increase the activity of any organ or function are said to stimulate it, while those which lessen the activity are said to depress MODE OF ACTION OF DRUGS. 21 it. Another condition induced by drugs is irritation, for although this term is often applied loosely as a synonym for stimulation, the two conditions are not identical. Stimulation is properly used to indicate an increase in the specialized function of a cell, producing, for instance, in the spinal cord an increase in the reflex excitability. Irritation, on the other hand, is used rather in reference to the changes in the conditions common to all forms of living matter, that is, it indicates a change in the nutrition and growth of the cell, rather than in the specialized functions. Irritation may thus be induced in all kinds of tissues and is the commonest change caused by drugs in the less differentiated forms such as the connective tissues and ordinary epithelia ; while stimulation is met with in the more highly specialized cells, such as those of the heart, nervous system, or secretory glands. In many instances the irritant action of drugs may be explained by their known reactions with the proteids of the cell ; for example, sub- stances which dissolve proteids, or precipitate them, or withdraw fluid from them, all tend to cause irritation when they are applied to living tissues. In other cases irritation appears to be induced through some chemical action the nature of which is quite unknown. When stimulation is prolonged or excessive, the protoplasm gener- ally becomes depressed and finally loses its activity entirely (paralysis). Some authorities have asserted that depression is invariably preceded by stimulation, and that stimulation sufficiently prolonged invariably leads to depression and paralysis. Both statements are too absolute, although they are true in the great majority of cases. For example, the action of atropine on the terminations of the cardiac inhibitory nerves is purely depressant. Even the most minute quantities of this alkaloid never increase the activity of these terminations, for if a quan- tity too small to paralyze them is ingested, it has apparently no effects whatever, and as the dose is increased, the first effect is paralysis. Depression, whether induced directly, or following on stimulation, has been shown in several instances to resemble the fatigue induced by the prolonged exercise of the normal organ, and it is probably true that depression and fatigue are, in all instances, identical in appearance, al- though not necessarily identical in cause. For example, the phenom- ena of fatigue of the terminations of the motor nerves in muscle re- semble exactly those induced by curara, but in the former the cause may be that the conducting substance of the nerve ends has been used up by the repeated passage of impulses, while in the latter the conduct- ing substance is so changed that it becomes incapable of transmitting stimuli to the muscles. The final result is, of course, the same ; there being no available conducting substance, impulses fail to reach the muscle. But the fatigued terminations rapidly recover, as conducting substance is reformed, while the curarized recover only when the poison is eliminated. In most cases an excessive dose of a stimulating poison leads to de- pression and paralysis. The cell becomes functionally dead, but if the failure of its function does not involve the death of the organism, it 22 INTE OD UCTION. may recover and reassume its ordinary function as if no stage of inac- tivity had intervened. Excessive irritation, on the other hand, leads to actual death and disintegration, from which there is no recovery. For example, the cells of the spinal cord are first stimulated, and later paralyzed by a large dose of strychnine, but this is not fatal to cold- blooded animals, and after a few days the spinal cord regains its nor- mal function, as the poison is eliminated. On the other hand, the in- jection of an irritant into the subcutaneous tissues causes dilatation of the vessels, effusion of fluid, and increased growth and rapid division of the cells. If only a small quantity be injected, this condition is recovered from, although it generally leaves evidence of its presence in the form of an increase in the fibrous tissue. But if the irritation be intense, the cells undergo degeneration and die, and an abscess is formed. The cells thus destroyed can never recover as the paralyzed ones do. They are either absorbed, or removed by the opening of the abscess, and their room is filled by the overgrowth of the neighboring tissues. ELECTIVE AFFINITY OF DRUGS. PROTOPLASM POISONS. Most drugs have an elective affinity for certain definite tissues. Thus, some attack the heart only, others the central nervous system and others the terminations of the motor nerves in muscle. Among the cardiac poisons again, some act on the ventricle, others on the auricle, and among the poisons of the central nervous system, some act primarily on the cortex, others on the medulla oblongata and others on the spinal cord. This elective affinity is not merely a question of degree, as is sometimes stated, for a drug which has a powerful action on the brain, may have no effect on the heart except when administered in such quantities as alter the physical characters of the blood. A drug may even alter different structures in diametrically opposite direc- tions. Thus, atropine depresses certain nerve terminations, but stimu- lates the brain, and curara, which paralyzes the peripheral terminations of the motor nerves, stimulates the spinal cord. In some instances the immunity of a cell to the action of a drug may perhaps be explained by the latter failing to penetrate into its interior, but this is not true in the great majority of cases. The fields of activity of different drugs vary greatly in extent. One may comprise only the terminations of the secretory fibres in the sweat glands (agaricin), while another, which affects these in the same way, may involve many other terminations in its action (atropine). Most poisons, however, while acting on a certain narrow area in small doses, extend the limits of their activity when larger quantities are ingested. Thus, a poison which acts in small doses on the medulla oblongata only, may, when exhibited in larger quantities, involve the spinal cord and the brain, and in still greater concentration may affect the heart and other organs. No poison is known that acts equally on all organs and tissues, but those which have a wide field of operation are often REMOTE, LOCAL, AND GENERAL ACTION. 23 known as protoplasm poisons. These paralyze any form of living mat- ter when they are brought in contact with it in sufficient quantity, but if they are injected into the blood and thus distributed equally through- out the body, they invariably select some special organ as the chief seat of their activity. This is exactly parallel to the behavior of chem- ical agents in the laboratory. For example, acetate of lead added to a solution of a chloride, or of a sulphate, precipitates it, but added to a mixture of the two, throws down more of the sulphate than of the chloride. Nitrate of silver, on the other hand, precipitates the chloride only. Acetate of lead may be compared to the protoplasm poisons, nitrate of silver to those with a less extensive field of action. As proto- plasm poisons affect a large number of different forms of living matter it follows that they alter the nutrition rather than specialized functions. Many of them cause irritation ; others are used to destroy or retard the growth of microbes and are known as disinfectants or antiseptics. REMOTE, LOCAL, AND GENERAL ACTION. Drugs change directly only those organs and tissues with which they come into immediate contact. But the alteration of one part of the organism very often entails that of another to which the drug may not have access, or for which it has no special affinity, because impulses are transmitted through the nerves, or changes are induced in the circula- tion and nutrition. Thus irritation of the skin may alter the rate of the pulse by impressions being transmitted by the cutaneous nerves and reflected along the inhibitory nerves of the heart. Similarly a poison that weakens the heart may induce disorder of the respiration, from the circulation being deficient in the medulla oblongata ; and depression of the brain may lessen the oxidation in the muscles, because it leads to lessened movement. These secondary changes, which are not due to the direct action of the drug on the organs concerned, are known as remote or indirect effects. The local action of a drug is that induced at the point of application before it enters the circulation, the general or systemic action is that due to its elective affinity for certain organs to which it is carried by the blood. The local effects are very often entirely different in nature from the general action, for a drug may act as an irritant at the point of application and as a depressant to the brain when it is carried to it in the blood. Local effects may be induced wherever the drug can be applied in the skin, the alimentary tract, the respiratory passages, and the other mucous membranes. They also occur in the subcutaneous tissues when the poison is injected hypodermically, and in any of the deeper organs and tissues which can be reached by the needle of the syringe. Local remedies may cause irritation, or may protect the sur- face from irritation, may depress the sensory end-organs and cause local anaesthesia, or lessen secretion, or alter the functions at the point of application in many other ways. They may also have remote effects, as has been mentioned. Many drugs have only a local action, because 24 INTRODUCTION. they are not absorbed, are absorbed in inactive forms, or are excreted or deposited as rapidly as they pass into the circulation, so that enough is not present in the blood at any one time to induce general effects. On the other hand, many powerful poisons have little or no effect at the point of application, but possess an elective affinity only for some organ to which they are carried by the circulation. THE RELATION BETWEEN CHEMICAL COMPOSITION AND PHARMACOLOGICAL ACTION. As the effect of drugs on living matter is conceived to be due to a chemical reaction between them, it might be inferred that those drugs which present a close resemblance in their chemical properties and com- position must induce similar changes in the organism. And this is true as a general statement, although the relation existing between chemical constitution and pharmacological action can be followed only a short distance as yet. For example, so many members of the methane series of chemistry depress the central nervous system that this may be re- garded as a general property of these bodies, just as they possess certain general chemical reactions, which distinguish them from the members of other chemical series. In the same way, the heavy metals resemble each other in their general effects on the organism, just as they react similarly to some chemical tests. But whenever an attempt is made to follow this relation in detail, the analogy breaks down, because factors which it is impossible to deduce from the chemical constitution, make themselves felt. Exactly the same thing occurs in chemistry ; for example, the heavy metals resemble each other in so many respects that it might be inferred that the sulphides would be of the same color, or that the chlorides would be equally soluble in water, but experiment shows that this is not the case. In the same way they resemble each other in many points in their effects in the organism, but it cannot be inferred from this that they will have the same effect on any given organ or in any given respect. A simple example of the very differ- ent effects in the organism of drugs which are closely related chemically, is offered by the action of the simpler members of the acetic acid series on the sense of smell. For formic, acetic, proprionic, butyric and valerianic acids can be easily distinguished by their odors, that is, they act differently on the terminations of the olfactory nerves, yet they form a homologous series of as closely related members as any chemical series can offer. They present certain differences in their chemical reactions, of course ; for example they vary considerably in the solu- bility of the salts they form with barium and calcium, and it is im- possible to explain, or to anticipate these variations from any consider- ation of their chemical constitution. If then their reactions with such simple and familiar bodies as calcium and barium cannot be anticipated, it would seem futile to attempt to foretell their behavior towards the infinitely more complex and less known protoplasm of the nerve ter- minations. CONDITIONS MODIFYING THE EFFECTS OF DRUGS. 25 A great deal of time and energy has been devoted to an attempt to bring the effects in the organism of certain metals (notably the alkalies) into relation with their atomic weights, their valency, electrical charges, and other properties, but no results are to be expected from these researches, so long as the ordinary chemical reactions of these bodies can only be formulated to a limited extent and imperfectly from such considerations. In particular, it seems of little interest to determine their exact relative toxicity, since there is no question that they do not all act on the same organs ; and if one act on the brain and another on the heart, one by its specific affinity for an organ and another by inducing physical changes in the fluids of the body, these differences are sufficient to nullify any relation which they may bear to each other in regard to the exact fatal dose. As has been stated, it may be inferred with some probability that any substance belonging to certain wide chemical groups will induce symptoms in the organism resembling in general characters those of the other members, provided always that it does not contain some radicle which renders it inactive, or gives it a more powerful action in some other direction. But the details of its action can be ascertained only by actual experiment, exactly as the details of its chemical be- havior can be known only by performing the necessary reactions ; and as there is no prospect of explaining the latter from its constitution at the present time, there is still less hope that much advance will be made in the near future in formulating the laws governing the details of its pharmacological effects. CONDITIONS MODIFYING THE EFFECTS OF DRUGS. The effects of drugs on the living organism are subject to some modi- fications in certain individuals, and under some conditions, which it is of importance that the physician should recognize, as the dose has to be altered when they are present. One of these is the Size and Weight. If the same amount of a poison be distributed through the tissues of a large individual as of a small one, less is contained in any given organ of the former and less effect is therefore observed. This has been ascertained chiefly in animal experiment, in which the effects of drugs can be estimated much more exactly than in man, but it un- doubtedly holds good for human beings also. Very large individ- uals, then, require a somewhat larger dose than ordinary persons, while in treating individuals of small stature, the dose has to be reduced. The Age of the patient has also to be taken into account in prescrib- ing. Children ought to receive much smaller doses than adults. The more powerful action of drugs in children is due in part to their smaller size, in part to the more active growth of certain tissues and to the less complete development of others, such as the central nervous system. The dose for a child is generally calculated according to Young's formula, in which a fraction obtained by dividing the age by the age + 12, is taken as the proportion of the adult dose required. Thus for a 26 INTRODUCTION. child of four years, the dose would be f ^ fs = ) i of the adult dose, for one of one year ( ^ i-^ = j ^ of the adult dose. According to another less used formula, the dose for a child is ascertained by divid- ing the adult dose by 20, and multiplying the result by the age. Brunton suggests dividing the dose by 25 and multiplying the result by the age at the next birthday. These formulae are not, however, inva- riably safe guides to follow in prescribing. For example, the narcotics, particularly opium and its preparations, must be given during the first years of life in much smaller quantities than are indicated by Young's rule, while alcohol may be administered in comparatively large doses. The usual dose advised has to be modified for children then, and may be taken as that suitable from 20-60 years. After this age is passed, it is again reduced somewhat, so that from 70-80 about f of the adult dose is advised, and after 85 it may be reduced to J. There are exceptions to this rule also, large doses of the purgatives, for ex- ample, being often necessary in old people. Sex. Women generally require somewhat smaller doses than men, because of their smaller size, and it is often stated, because their tissues react more strongly to some drugs, though this has not yet been satis- factorily established. Temporary conditions also influence the activity of drugs. Thus after a mealy a poison is absorbed more slowly from the stomach than when it is taken fasting, and any local irritant action is also less marked, because the drug is diluted by the contents of the stomach. Irritation of the stomach and intestine may also modify the effects of drugs ; thus in some forms of dyspepsia the absorption is slower than usual and little effect may be induced by the ordinary dose, while irri- tant drugs naturally cause more disturbance of the digestion in these cases. On the other hand, a slight congestion of the stomach and bowel tends to promote absorption, and it has been found that more of a heavy metal is absorbed when it causes some destruction of the mucous membrane than when it is given in smaller quantities. Vomiting and diarrhoea, of course, tend to lessen the action of drugs by re- moving them rapidly from the alimentary canal. During pregnancy, purgatives have to be used with great care, be- cause they induce congestion of the pelvis, and may lead to abortion. Drugs acting on the uterus, or inducing a marked fall of blood pres- sure, are to be avoided because the former may cause the evacuation of the uterine contents, while the latter may lead to asphyxia of the foetus. Many drugs pass from the mother to the child, and this is to be borne in mind, as quantities which are insufficient to poison the former may have more serious effects on the latter. During lactation, it is impor- tant to remember that active bodies may be excreted in the milk, and may either act on the child or render the milk distasteful to it. In menstruation, purgatives are to be avoided, as they tend to increase CONDITIONS MODIFYING THE EFFECTS OF DRUGS. 27 the flow, and all very active drugs are to be used with care or aban- doned temporarily. The Time of Administration has also some influence on the effects of drugs. The body is generally more resistant in the morning than in the evening, especially in the case of narcotic drugs ; thus a dose of a soporific which may have little or no effect in the early hours, induces sound sleep when given in the evening, because the brain is already fatigued and depressed. Idiosyncrasy is used to denote an unusual effect for which no expla- nation can be found. Some persons react more readily than usual to the ordinary dose, while in other instances a much larger quantity can be taken without any effect. Others, again, show symptoms which are entirely different from, and which may, in fact, be diametrically opposite to those ordinarily observed. These idiosyncrasies are naturally more frequently seen, and are better known when they arise from widely used drugs. Thus the modern antipyretics have so often induced ab- normal symptoms that these are well known, but it is not improbable that if other drugs had been used, or rather abused, to the same extent, they would be found to induce unusual reactions in an equally large number of individuals. An idiosyncrasy, as has been said, cannot be explained in the present state of knowledge, but some conditions which have been termed idiosyncrasies are probably due to abnormally rapid, or to retarded absorption or excretion. Idiosyncrasies are not con- fined to human beings, for not infrequently one animal reacts quite differently from others of the same species. As has been mentioned, one form of idiosyncrasy consists in the fail- ure of the individual to react to the ordinary dose of a drug. This is known as Tolerance, and this particular form of idiosyncrasy may be termed congenital tolerance. Certain species of animals tolerate quan- tities of drugs which would be fatal to others of the same size. In fact, so frequently is this the case that it is impossible to determine the fatal dose of any drug on an animal from experiments performed upon others of a different species, even though it be nearly related. One of the most remarkable examples of this form of tolerance is met with in the hedgehog, which resists large doses of many very active poisons. Another well-known example is the tolerance of the rabbit of large quantities of atropiue. A form of tolerance which is a matter of everyday observation is that induced by the prolonged use of a drug, which has been called acquired tolerance, or mithridatism, from the belief that Mithridates protected himself in this way from the danger of poisoning. The most familiar example of this form of tolerance is that acquired for tobacco (nicotine) ; the first cigar often induces violent poisoning, but if a habit be formed, considerable amounts of nicotine may be absorbed without apparent harm, not because the absorption is retarded, or the excretion is accelerated, but because the tissues become accustomed to the presence of small quantities of nicotine, and thus fail to react to it. Nicotine, in fact, becomes a normal constituent of the tissues. This tolerance is entirely 28 INTRODUCTION. different from the immunity induced by toxalbumins (see Ricin), and it is desirable that the two terms should be kept distinct. Very often while tolerance for a poison is established in certain tissues, others suffer from the prolonged use of excessive quantities ; for example, although the seasoned smoker does not suffer from the nausea and vomiting which followed his first essay, other organs may in course of time become involved, such as the heart or the eye. It is to be noted that tolerance is soon lost if the drug be discontinued for some time. This is of great importance in cases of opium-eating, for a person who has taken opium for a long time acquires a tolerance for the drug, so that sometimes enormous quantities are required in order to induce the ordinary effects, but if the habit be discontinued for some time the tolerance is lost, and a dose which would formerly have had little effect may now induce dangerous poisoning. The prolonged use of one drug may establish tolerance for others of the same class. Thus chronic drunkards are not influenced by large quantities of alcohol, and are also more resistant to the action of chloroform than ordinary persons, this being due to the fact that chloroform and alcohol act on the same nerve cells in the same direction, and probably induce the same changes in the protoplasm. The Cumulative Effect of drugs is another phenomenon caused by their prolonged ingestion. Small doses of certain drugs taken repeatedly for some time eventually cause symptoms which are much more marked than those caused by a single small dose. In many instances this seems due to the accumulation of considerable quantities in the tissues. The absorption may be more rapid than the excretion, and each new dose thus adds to the total quantity in the blood and organs more than is lost in the same time by excretion. The classical example of cumu- lative action is that of digitalis, but it is much more frequently induced by such drugs as mercury, arsenic, or the iodides, for the so-called chronic poisoning induced by these is really an example of cumulative action. It has been suggested that cumulative action is not really due to the accumulation of the drug in the tissues, but to a summation of a prolonged series of effects of the same kind ; but although the increase of the drug in the organs has not been proved in all instances, it seems probable that this is the explanation in the great majority of cases, perhaps in all. Cumulative action may occur along with tolerance, as has been stated. Thus the tolerance of certain tissues for nicotine does not protect others from the effects of the abuse of tobacco, Synergists.- The presence of another drug having the same effects in the body often increases the action of a remedy to an unexpected extent. This is the ground for the prescription of several remedies acting in the same way. 1 For example, several purgatives prescribed together often act more efficiently than any one given in quantity equal to all of them. It is quite impossible to explain this except by assuming that, although all are alike in their chief features, they differ in the details of their reactions, so that parts of the alimentary 1 The less important ones are sometimes termed adjuvants. CONDITIONS MODIFYING THE EFFECTS OF DRUGS. 29 canal which might escape one are affected by another, and the mixture thus acts more universally than any one of the components. It must be added that, although the greater efficiency of the mixture is attested by the general belief of physicians, no very satisfactory researches on the subject have been carried out as yet. On the other hand, a drug may fail to elicit any symptoms if an antagonistic substance be present in the body. Thus in cases where a powerful nervous depressant, such as chloroform, has been inhaled, strychnine may have little or no effect on the spinal cord in doses which would normally increase the reflexes to a marked extent. In the same way, if the terminations of the inhibitory fibres of the heart are paralyzed by atropine, a poison which normally slows the heart by stimulating these terminations will have no such effect except in very much larger doses. Similar modifications of the effects of drugs may be induced by poi- sons induced by pathological changes in the tissues, or by an unusual state of irritation or of depression of the tissues themselves. For ex- ample, in hot weather and in tropical climates, purgatives are found much more efficient than in colder climates, either because there is some poison which acts along with the purgative, or because the mucous membrane is more irritable than usual. That some such factor is present in these conditions, is shown by the frequent occurrence of diarrhoaa without the use of drugs. Similarly when an antagonistic poison is formed in the tissues in the course of a disease, a drug may have little or no effect ; so that if the inhibitory cardiac terminations are paralyzed by disease, the heart cannot be slowed by muscarine or digitalis. Pathological conditions very often modify the effects of drugs to a very considerable extent, and in a way which cannot be explained at present. For example, the antipyretics reduce the temperature in fever, but have no effect on it in health ; the bromides lessen the con- vulsions in epilepsy, but have much less effect in depressing the brain in normal persons. The question may therefore be raised whether the examination of the effects of drugs in normal animals is of much value in indicating their therapeutic action. But in reply it may be said that in a large number of instances drugs are given, not in order to act upon the diseased tissues, but upon healthy ones. The object of the therapeutist is very generally not to restore the diseased tissue, but to relieve it from work, and to allow it rest so as to promote its restoration by nature. For instance, in disease of the cardiac valves, drugs are given not with the object of restoring their integrity, but to act upon the healthy heart muscle, and to obviate the disturbance of the circulation which is caused by the destruction of the valves. In inflammation of the kidneys, the physician seldom attempts to reduce the inflammation by the action of drugs on the cells involved, but confines his attention to removing by other channels the products of tissue waste, which would normally be excreted by the kidney. So that in most instances drugs are given to act on normal tissues, or on 30 INTRODUCTION. tissues which are so little affected by disease that they react to reme- dies in the same way as the normal. In other cases in which the remedy acts on the cause of the disease or on the diseased tissue, its introduction is due to clinical experience only. Thus quinine destroys the organism of malarial fever, but this could never have been antici- pated from its action on the normal tissues, and could only be discov- ered by experiments on the organism, or rather by experiments on persons suffering from the disease, as the organism has been recog- nized only of late years. METHODS OF ADMINISTRATION. The effect of a remedy is often determined very largely by the method in which it is administered. As regards the local action, this is sufficiently obvious, for an irritant applied to the skin could scarcely be expected to cause the same symptoms as if it were applied to the stomach and intestine. But the same holds true for the general action in most instances, because some tissues and organs absorb much more rapidly than others, and a larger quantity of the drug therefore passes through them into the blood in a given time. Thus, if a poison which is absorbed slowly be rapidly excreted, so little of it may exist in the blood and tissues at any given time that no effects are induced, while if it be rapidly absorbed, the same dose can exert some action before it is excreted. Drugs are applied for their Local Action to the skin, to the mucous membranes of the alimentary, respiratory, and genito-urinary tracts, and to the conjunctiva and cornea. Not infrequently they are injected by means of the hypodermic needle into the subcutaneous tissues for their local effects, and the attempt is continually being renewed to treat even the deeper tissues and organs locally by the injection of remedies into them. The objects of local medication are very diverse, and can be treated of only in connection with the individual drugs. The methods of application are also so numerous that only a few of the chief can be mentioned. Drugs intended for application to the skin are often formed into salves or ointments (unguenta) by mixing them with oily or fatty substances, which adhere to the skin and do not dry up, and which in addition to serving as a means of applying an active substance, protect the surface from the air and from irritation. Other preparations for application to the skin, such as the plasters (ernplastra), resemble the ointments in their general characters, but also give mechanical support, and bind surfaces together from their being spread on paper or cloth, which thus serves as a flexible splint. The collodions and cerates resemble the plasters, the oleates the oint- ments. In addition to these special preparations, drugs may be ap- plied to the skin in solutions, or as powders, or solid masses may be used to cauterize it. The methods of applying drugs to the alimentary tract and to the lungs for their local action are for the most part similar to those used METHODS OF ADMINISTRATION. 31 for drugs which are intended to be absorbed. The mouth and throat may be washed out with solutions, which are gargled (gargarismata), or may be treated with powders, or lozenges (trochisci), which are slowly dissolved and thus permit of a more prolonged and constant action in the mouth than is possible if the drug be swallowed imme- diately. The nose may be washed out with solutions of active drugs, or powders may be drawn into the nostrils as snuffs ; the latter often cause sneezing, and are sometimes known as sternutatories, or errhines. The larynx may be treated locally by the application of powders or of very small quantities of fluids by means of the laryngoscopic mirror and probe. Solutions are generally used for application to the con- junctiva, but a more permanent effect can often be obtained from the use of ointments or powders which are less liable to be washed away by the tears. The urethra, vagina and uterus are treated by the in- jection of solutions, or by ointments and powders. Bougies, which are occasionally advised, are formed by incorporating an active drug in some substance which is solid at ordinary temperatures, but melts when introduced into the organ and allows the drug to come into con- tact with the surface. The rectum may similarly be treated by the in- jection of drugs in solution or suspension (enemata), or by the use of suppositories. Drugs are not infrequently applied by the rectum in order to elicit their action after absorption, but much oftener for their local action on the bowel. Enemata may be either large (a pint or more) or small (25 c.c., \ 1 fl. dr.). The large enemata are used either to wash out the intestines, and may then contain an antiseptic or astringent, or to induce peristalsis and evacuation of the bowel, when they are made up of water with or without soap or other slightly irritant substances. The small enemata are used chiefly to induce evacuation, and contain more irritant substances, such as glycerin alone or along with some more active body (see uses of the vegetable purgatives). The suppositories are formed of cacao-butter, which is solid at room temperatures, but melts at the temperature of the rectum. All the visible mucous membranes may also be cauterized by the application of a solid rod of a corrosive for a short time. Drugs whose General Action is to be elicited after their absorption are given by the mouth, except when some special character in them or in the disease renders some other method preferable. They may be given by the mouth in solution in water, alcohol, oils, or other more or less indifferent bodies. The disagreeable taste of many remedies, however, often precludes this method, and these may be ordered in the form of pills, or in capsules, which are formed of gelatin or similar substances and are dissolved in the stomach and intestines. Very often the disagree- able taste may be concealed by the addition of sugar, or of some strongly tasting but agreeable body such as a volatile oil. Insoluble drugs may be given as powders, as they have little or no taste. Powders are also used as a means of administering soluble drugs, if they have not a dis- agreeable taste and have no marked local action, but very deliquescent drugs should not be given in this form. Insoluble drugs are sometimes 32 INTRODUCTION. ordered in suspension in mucilaginous fluids ; and oils, which are dis- tasteful to many people, may be given mixed with water and gums (emulsions). The rate of absorption from the alimentary canal varies greatly with different drugs and also with the form, in which they are adminis- tered. The first point will be treated of in connection with the indi- vidual drugs. As regards the second, it may be stated that drugs are more rapidly absorbed when they are swallowed in solution, and that when much inert and insoluble matter is associated with them, their absorption is much retarded. Thus, common salt passes more rapidly into the blood when it is dissolved before being taken than when it is swallowed dry, and morphine is absorbed much more quickly when it is administered pure than when, as in opium, it is mixed with a mass of gums and other bodies. This fact is taken advantage of in practice by giving drugs in solution when rapid absorption is desirable, and by giv- ing less pure forms when the local action on the stomach and bowel is .to be elicited. The more concentrated the solution, the greater is the irritant action on the stomach, and thu? where irritation of the stomach is desired, either the solid drug or a strong solution is given ; but as a general rule the local action on the stomach is to be avoided, and drugs are therefore ordered in as dilute solution as is possible without increasing the bulk to too great an extent. It is to be noted that drugs which are insoluble in the test-tube may be rendered soluble by the action of the gastric and intestinal juices, while many which are given in solution, are thrown down in the stomach in the form of insoluble albuminates. The great mass of drugs absorbed from the stomach and intestine is carried to the liver before reaching the general circulation, and this is of great importance in determining their effects in the body, as some of them are retained in that organ, and are either entirely destroyed or escape so slowly that they have no perceptible effect. Another important method of administering drugs for their general action and also for their local effects is by inhalation into the lungs. Only volatile drugs can be used thus for their general action. They are absorbed very rapidly owing to the extensive surface to which they are applied, and also because volatile substances penetrate the tissues more readily than others. The best examples of inhalation are offered by the general anaesthetics, chloroform and ether. Most substances absorbed by the lungs are also excreted by them, and this leads to an important practical point in regard to the anaesthetics. For the passage of gases or vapors through the lining epithelium of the alveoli depends in most instances * upon their partial pressure, that is, upon their con- centration in the air and blood respectively. Accordingly, when the air contains more chloroform vapor than the blood, the anaesthetic passes into the blood, but as soon as the condition is reversed, and the blood contains more chloroform than the air of the alveoli, it commences to 1 Such gases as oxygen and carbon monoxide, which form chemical combinations with the haemoglobin, are of course exceptions. METHODS OF ADMINISTRATION. 33 pass backwards. The more concentrated the vapor inhaled, the more chloroform is contained in the cubic centimeter of blood, and the greater is the action on the nervous centres and the heart. Less volatile substances are sometimes inhaled into the lungs for their local action, and even non-volatile bodies suspended in a spray of vapor may be thrown into the respiratory passages, but it may be questioned whether these last really reach the alveoli except in traces. Drugs are also applied to the skin in order to elicit their general action. Volatile bodies are certainly absorbed by it, although much more slowly than by the lungs or by the stomach and intestine. Solu- tions in water of non-volatile drugs are not absorbed from the skin, but solutions of certain remedies in alcohol, oils, fats, ether, and some other substances which are capable of dissolving or mixing with the fatty covering of the skin, are absorbed fairly rapidly if they are rubbed in thoroughly. This method of application (inunction) has been used chiefly for the absorption of mercury, as the local action on the stomach and bowel is thus avoided. (See Mercury.) Alkaloids do not appear to be absorbed by the skin even when dissolved in oils or alcohol. An entirely obsolete method of application is the endermic, in which the epidermis was removed by a blister, and the remedy then applied to the exposed corium. The hypodermic method is of comparatively recent origin, but is being more widely used every year. In it drugs are injected through a fine hollow needle into the subcutaneous, or, in the case of more irritant substances, into the muscular tissue, where they meet with fewer sensory nerves. Absorption occurs more rapidly than when drugs are given by the mouth, the local action on the alimentary canal is avoided, and the physician is more certain that the whole of the remedy is effective, provided it is soluble and is not pre- cipitated at the point of injection. At the same time, the method has certain drawbacks, the chief of which are the pain of the injec- tion and the danger of injecting a powerful remedy into one of the subcutaneous veins. Hypodermic injections should be made only by the physician or trained attendant, for incalculable injury has been done by entrusting patients with the syringe, particularly for the injection of morphine and cocaine. The needle and syringe ought to be disinfected, and the substance injected should be aseptic, and this renders the method inconvenient. As a general rule, solutions in water or in dilute alcohol are used for injection, but the insoluble salts of mercury have also been injected, suspended in oil (see Mer- cury). Irritant drugs are to be avoided as far as possible, as they cause great pain, swelling and sometimes suppuration, even when the injection has been carried out aseptically. Hypodermic injection is used very largely to elicit the general action of a remedy, but also for the local effects, as when cocaine is injected in order to produce local anaesthesia. Solutions of inert bodies have also some anaesthetic action, probably owing to their mechanical action on the sensory nerve fibres. As the absorption from the subcutaneous tissues is so much more rapid 3 34 INTRODUCTION. than that from the stomach and intestine, when the drug is in perfect solution the dose has to be reduced. As a general rule, about one- half of the ordinary amount is sufficient. Deeper injections are sometimes made for their local action on the organs. Thus, antiseptics have been injected into lung cavities, caustics have been injected into tumors, and direct applications have been made to the nerves in sciatica and other similar disorders. Intravenous injection is the most certain method of bringing drugs into the circulation and tissues, and is at the same time the most rapid. It is, therefore, very largely used in experiments on animals, but has generally been considered too dangerous for therapeutic purposes in man. Baccelli has, however, recommended it highly in recent years in cases of emergency, in which the immediate action of a remedy is required. In pernicious malaria, and in syphilis when an important organ is threatened, he has injected small quantities of quinine and mercury with great success. The dose must be very much smaller than that employed by the mouth, but it is impossible as yet to state exactly what fraction will induce the same effects. Drugs are occasionally applied by the rectum for their general action, as has been mentioned. The local effects on the stomach are avoided by this method, and morphine and opium are, therefore, not infrequently administered thus. The rate of absorption from the rectum as com- pared with that from the stomach and bowel is still a disputed point, and some physicians recommend that the dose be reduced to three- fourths, while others recommend one and one-half times that given by the mouth. Drugs are not administered by the other mucous membranes for their general effects, but it must not be forgotten that symptoms may arise from their application to them for their local action. Similarly, drugs applied as dressings to wounds or abrasions have very often given rise to severe or fatal poisoning from being absorbed into the blood and tissues. THE CHEMICAL CHARACTERS OF DRUGS. An enormous number of substances induce changes in the living organism, and have, therefore, to be recognized in pharmacological treatises. Many of them are comparatively simple chemical com- pounds, and require no general description here, but less attention is paid in ordinary chemical text-books to certain groups of active poisons, and some note must be taken of their general properties. In the inorganic materia medica are found many salts, bases, and acids, and a few uncombined elements, such as mercury and phosphorus. Organic chemistry offers a large and ever-increasing number of arti- ficial compounds which belong to almost every one of the divisions recognized in chemistry. The hydrocarbons, alcohols, ethers, phenols, ketones, aldehydes, acids, and many others, contribute active agents, and in fact most of them are represented by one or more members in therapeutics. They may all be regarded as sufficiently known by stu- THE CHEMICAL CHARACTERS OF DRUGS. 35 dents who are prepared to study pharmacology with profit, but some substances, obtained chiefly from plants, require further mention. The first group of these is formed by the Alkaloids, which are substituted ammonias, and have a more or less strongly alkaline re- action, so that they are often known as the vegetable bases. They contain carbon, hydrogen, nitrogen, and, as a" general rule, oxygen, although some of them, such as coniine, are devoid of it. Like am- monia, they combine with acids readily without eliminating hydrogen, arid the salts thus formed resemble those of ammonia in many respects, among others in being thrown out of combination by the fixed alkalies. The term alkaloid is often restricted to compounds of pyridine and quinoline, but this narrow definition cannot be maintained in treating them from the pharmacological point of view. It is true that most of the vegetable alkaloids whose constitution is known are derived from pyridine, quinoline and isoquinoline by the addition of hydrogen, and generally by the substitution of one or more of the hydrogen atoms by side chains of greater or less complexity. CH CH HC/ \CH Hd\>H N c: Pyridine. Quinoline. But others appear to be derivatives of the pyrrol and oxazine groups, while in others the nitrogen is attached to radicles belonging to the methane or open-chain series, as in CH(OH) 2 CH 2 N(CH 3 ) 3 OH, which is generally regarded as the formula of muscarine. Another series of bodies, which may be regarded as alkaloids, although they differ from the others in many respects, are derivatives of aniline, and are artificial products. CH o HC HC /\ y\ C-NH 2 HC / \CH CH HCk JCH Hc l ICH N Pyrrol. Aniline. Oxazine. These aniline derivatives bear some relation to the vegetable bases in their action, but are equally or more nearly related to the benzol series, so that they may be regarded as connecting links between these two classes of bodies. Finally the purine bodies (see Caffeine group) may be mentioned in this connection, although their chemical structure scarcely permits of their being numbered among the true alkaloids. Some of the vegetable alkaloids have been formed synthetically in the laboratory, and the constitution of some of the others is perfectly well known, but many of them have not yet been isolated, and there are probably others whose existence is not even suspected. These vege- table alkaloids occur in almost all parts of plants, although they are 36 INTR OD UCTION. found in greatest abundance in the seeds and roots. The same alka- loid is often found in most of the plants of a genus, or it may occur in one or two species of a genus and in other plants which are in no way related. Very often more than one alkaloid is found in a plant, and these may differ entirely in their action on animals, although not in- frequently all the alkaloids of a plant resemble each other in their effects. The alkaloids are found almost exclusively in dicotyledonous plants, only one or two being known to exist in the monocotyledons. Muscarine is found in the fungi, and quite recently alkaloids have been isolated from the suprarenal capsule of animals and from the skin of the salamander. The alkaloids are very often only slightly soluble in water, but form salts which are generally more soluble. Many of the bases are dissolved in ether, chloroform and amyl alcohol, while the salts are in- soluble in these. Both bases and salts are generally fairly soluble in alcohol. The alkaloids are precipitated from solution by a large num- ber of reagents, of which the most important are the chlorides of platinum and of gold, tannic acid, phosphotungstic and phosphomo- lybdic acid, the double iodides of potassium and mercury, and of po- tassium and cadmium, and iodine held in solution in water by potassic iodide. The hydrates and carbonates of the alkalies and the alkaline earths precipitate the alkaloids from solutions of the salts in water, a point of some importance in prescribing these bodies. In cases of poisoning when the alkaloid has been taken by the mouth, it may be precipitated in the stomach by dilute alkalies or better by tannin solu- tions. The poison should then be removed by inducing vomiting or by washing out the stomach with the stomach tube. Another important class of vegetable poisons is formed by the Glu- cosides (glycosides), or saccharides, which are esters (compound ethers) composed of sugars and hydroxyl substances, and which liberate sugar when they are heated with acids, or sometimes with alkalies, or when certain unorganized ferments act on them. The sugar formed in this way is often glucose, but not invariably so ; the other decompo- sition products have been identified only in a few instances. Many of the glucosides contain only carbon, hydrogen and oxygen, a few have nitrogen in addition and one or two sulphur. In some instances the remainder, after the sugar is split off, is an alkaloid, e. g., solanidine. Glucosides differ greatly in their solubility in water and alcohol ; com- paratively few of them are soluble in ether. Some of the glucosides are powerful poisons, others have little or no action. Resins, an ill-defined group, are found in many plants, and are characterized by their smooth, shining fracture, and by their insolubility in water and solubility in ether, chloroform, volatile oils, benzol and, in many cases, in alcohol. They seem to be formed in plants by the oxi- dation of volatile oils, and are often acid or anhydride in character, while others are apparently alcohols or esters. The resins are almost invariably composed of several different substances mixed together. Many of the resins are local irritants, and some are poisonous in com- PHARMACOPEIAS AND PHARMACOPCEIAL PREPARATIONS. 37 paratively small quantity from the powerful action they exert on the intestine. Oleoresins are solutions of resins in ethereal oils, which lend them a characteristic odor and taste. The term ' Balsam ' is often used as synonymous with oleoresin, but most writers restrict it to those oleoresins which contain ben- zoic and cinnamic acid along with other constituents. (See Benzoic Acid.) Gumresins are mixtures of resins and gums, generally containing some volatile oils. They are insoluble in water, but the resin is suspended in it by the gum. On the other hand, the resin is dissolved by alcohol, while the gum remains insoluble. Gums are amorphous, transparent substances, composed of carbohy- drates of the formula C 6 H 10 O 5 and are thus nearly related to cellu- lose and starch. Some of them are soluble in water, while others merely swell to a jelly in it ; they are insoluble in alcohol. They generally occur in plants in combination with calcium, magnesium or potassium ; they have no poisonous action, but form a protective cover- ing for irritated surfaces, and are largely used to suspend in water sub- stances which are insoluble in it, such as resins and oils. Volatile oils occur in plants in large numbers. (See page 61.) Many Acids which are of pharmacological and therapeutic interest are obtained from plants, but it is unnecessary to enter into a descrip- tion of their properties here. Fats and oils, sugars, starch, proteids, coloring matter, ferments and other bodies which occur in plants, and are contained in many of the preparations used in therapeutics, are not generally possessed of any action of importance. Those which are active in the body will be described individually. Finally many of the active principles of plants are entirely unknown or have been only partially examined. Among these are a number of substances which have little in common except their bitter taste and which are known as Bitters. THE PHARMACOPEIAS AND PHARMACOPCEIAL PREPARATIONS. Almost all governments have found it necessary to regulate the preparation of drugs used in therapeutics, and for this purpose issue at intervals codes of instructions defining the characters of the drugs and giving the exact formulae according to which they are to be prepared for use. In the United States, where the government has not un- dertaken this as yet, a code has been prepared by a voluntary asso- ciation of physicians and pharmacists. These codes are known as Pharmacopoeias, and some differences exist between those of different states, although the most important drugs are found in all of them. All the drugs used in therapeutics are not found in the pharmacopoeias, for these are issued only at intervals of several years, and in the mean- 38 INTRODUCTION. time large numbers of remedies are introduced, used for a few months, and pass into oblivion. Even when a drug maintains its position for many years, and promises to be a lasting addition to therapeutics, it often fails to be admitted to the official code, while others of older standing, which are comparatively seldom used, and which might be omitted without loss, are kept on the list. This conservative tendency of the compilers of the pharmacopeias has its disadvantages, but at any rate tends to withhold official sanction from the innumerable ephemeral products of chemical industry. The official definition of therapeutic substances is of advantage to both physician and pharmacist, as it assures the former that the drug he prescribes will have a uniform quality, wherever in the country it is dispensed, while the pharmacist is saved from the continual preparation of remedies in different forms, by their being prescribed in one recognized strength. The pharmacopeias contain a large number of pure substances such as salts, acids, bases, alkaloids, and these require no further description. On the other hand, many of the drugs are given in an impure form, either because the active principle is unknown, or because its isolation is attended with difficulty and expense. Thus many of the vegetable remedies are presented in the pharmacopoeias as solutions or solids which contain not only the active principle but gums, sugars, coloring matter, and many other impurities. These are provided in different forms to allow of variation in their administration. In addition, the pharma- copoeias contain a number of official prescriptions, that is, mixtures of active substances in such proportions as are ordinarily prescribed. These are generally designated by the addition of compound (compo- situs) to the name of the chief ingredient. Most pharmacopoeias continue to use Latin in the titles of the drugs, and this is not due to mere pedantry or conservatism, as is often stated. For the popular name of a drug is often used for several different substances, as, for example, hellebore, while the Latin name in a prescription indicates that drug which is known by the term in the pharmacopoeia. In the same way it is found necessary to maintain Latin terms in botany and zoology in order to define accurately the species. Many crude or unprepared drugs are found in the pharmacopoeias, such as leaves, roots, flowers, or even whole plants. These are used chiefly for the preparation of other more readily applicable remedies, but are sometimes prescribed as powders or in pills. The following preparations l are official : a. Aqueous Preparations. Aquse, medicated waters, generally contain only traces of some volatile substance, such as an ethereal oil or chloroform, in solution in water, and these are used in prescriptions as more agreeable to the taste and smell than pure water but have no farther effect. In the U. S. P. the solutions of 1 The student is advised to omit the following list for the present, and to refer to it only as he takes up the preparations of the individual drugs. Most of these prepara- tions are found in both pharmacopoeias. Those which occur only in the British are indi- cated by B. P., while those which are confined to the United States are marked U. S. P. PHARMACOPCEIAS AND PHARMACOPCEIAL PREPARATIONS. 39 chlorine, ammonia and hydrogen peroxide are also included under aquse, but these are used only to elicit the specific effects of these drugs and are power- ful poisons. In the B. P. these strong solutions are included in the liquores. Liquores (U. S. P.) are solutions in water of soluble substances which are not volatile. The official solutions of powerful poisons are often one per cent, in strength. Liquores (B. P.) are solutions in the widest sense, in water, alcohol, or other fluids. The dissolved substance may be volatile or non-volatile. The "concentrated solutions" (B. P., Liquores Concentrati) are not, as might be supposed, condensed by evaporation. They resemble infusions and decoc- tions in most respects. Decocta, or decoctions, are impure solutions of vegetable principles, which are obtained by boiling parts of plants in water. Jn/wsa, or infusions, are solutions obtained by soaking parts of plants in water, which may be hot or cold, but is not kept boiling. Infusions and decoctions are weak preparations and decompose rapidly so that they are used only when recently prepared. Misturse (U. S. P.), or mixtures, are preparations in which substances in- soluble iu water are suspended in it by means of gums or similar viscid sub- stances. Misturse (B. P.) include a number of preparations in which insoluble bodies are suspended in water by means of gums or syrup, but one mixture contains only soluble bodies. Emulsa (U. S. P.), emulsions, are formed by suspending oils in water by means of gums or other viscid bodies. The B. P. contains no official emul- sions, the corresponding preparations being known as misturse. Mucilagines, mucilages, are solutions in water of gums, starch, and sim- ilar bodies. Syrupi, syrups, are strong solutions of sugar in water, which may be used alone, or may be impregnated with more active bodies. Similar preparations formed with honey instead of syrup (sometimes known as mellita) are official, as Mel Rosse (U. S. P.), Mel Boracis (B. P.). A solution of honey and acetic acid is known as oxymel in the B. P. (Oxymel Scillse). Lotiones (B. P.), lotions, or washes. This term is used to designate two preparations of mercury, the black and yellow wash. b. Alcoholic Preparations. It is to be noted that in these preparations the menstruum (alcohol) is not an indifferent body as in the aqueous preparations ; the effects of some of this class are undoubtedly due rather to the alcohol than to the dissolved substances. Spirit us, spirits, are solutions of volatile bodies in alcohol, and often owe their chief action to the solvent and not to the drug contained in it. Elixiria (U. S. P.), elixirs, differ from spirits chiefly in containing sugars, which are added in order to give them taste. Tincturse, tinctures, are solutions in alcohol of medicinal substances, which are generally formed by soaking parts of plants in it. They contain both volatile and non-volatile ingredients, but the latter are generally the more important. Fluidextracta (U. S. P.), Extracta Liquida (B. P.), fluid extracts, are prepared from plants by forming solutions in water or more frequently in alcohol, and evaporating them until the solutions contain as many cubic centimeters as the original crude drugs weighed in grammes ; that is the volume of the fluid extract corresponds to the weight of the crude drug. The tinctures and fluid extracts are the most commonly used liquid preparations, and most of the important drugs are prepared in one or both of these forms. Vina, medicated wines, are solutions of active substances in wine or in dilute alcohol. 40 INTR 01) UCTION. Sued (B. P.), the juices of fresh green plants, obtained by pressure. Some alcohol is added to preserve them from putrefaction. c. Other Fluid Preparations. Glycerita (U. S. P.) or Glycerina (B. P.) are solutions of medicinal sub- stances in glycerin. Collodia, collodions, are solutions of medicinal substances in collodion. (See Part VI.) Aceta, or medicated vinegars, are solutions of medicinal substances in vinegar or acetic acid. Linimenta, liniments, embrocations, are preparations in which active rem- edies are dissolved or suspended in dilute alcohol, oils, or water. They gen- erally contain an oil or soap and are intended to be applied to the skin. d. Solid and Semi- Solid Preparations. Extracta, extracts, are formed from solutions such as tinctures, decoctions, or infusions by evaporation, which is continued until there remains a solid mass. The extracts thus contain all the substances which are taken up by the solvent, except those which are driven off or decomposed by the temper- ature at which evaporation is carried on. Pilulse, pills, are globular masses of small size, such as admits of their being easily swallowed. They are formed from extracts, or from powders, by the addition of some substance to give them the necessary cohesion and consistency. Pills generally weigh 0.1-0.3 G. (2-5 grs.). The U. S. P. de- termines the composition and size of the official pills, so that the dose can be modified only by ordering several pills to be taken at one time. The B. P. leaves the pills unformed, so that they may be prescribed of any size. T 1 Pilulse of the B. P. really correspond not to the Pilulse, but to the Massse * the U. S. P. Massse (U. S. P.), masses, are preparations made up of the proper consist- ency for pills. They are invariably prescribed in the form of pills. Confectiones, confections or electuaries, are soft, solid preparations consist- ing of sugar or honey impregnated with some more active body. Suppositoria, or suppositories, are intended for insertion into the rectum, urethra, or vagina, and are, except in one or two cases, formed by mixing the active ingredient with cacao-butter. (See Part VI. ) Suppositories for the rectum are conical in shape and weigh about a gramme (15 grs.). Those for the urethra are of the same weight, but are pencil- shaped, while the vaginal suppositories are globular, and weigh about 3 grammes (45 grs.). Pulveres, powders, are simply dry substances in a state of fine division. Most of the official powders are mixtures of several active bodies. Triturationes (U. S. P.), trituratibns, are formed from powders by diluting them with nine parts of sugar of milk. Trochisci, troches, or lozenges, are solid masses, generally of a flattened shape, and consist of powders or other bodies, incorporated in sugar and gum. A very friable form of lozenge known as Tabellse, or tablet triturates (not official), is formed by pressing in moulds a mixture of powdered sugar and drugs, slightly moistened with alcohol. Lamellse, (B. P.), or discs, are small discs formed of gelatin with some gly- cerin, each weighing ^"sV g r - They are impregnated with an active drug, and are applied to the conjunctiva in order to elicit the local effects. Unguenta, ointments, salves, are soft, oily substances which are applied to the skin by rubbing. (See page 49.) Oleata, solutions in oleic acid resembling the ointments in appearance and uses. Cerata (U. S. P.), cerates, resemble ointments, but are rendered harder by the addition of wax. (See page 51.) CLASSIFICATION OF DRUGS. 41 Emplastra, plasters, are adhesive bodies of a still harder consistency than cerates, and soften only when heated. (See Part VI.) ChartsK, papers, are preparations of active substances which are spread in a thin layer upon paper, or are incorporated in it by dipping sheets of paper into a solution. UNOFFICIAL PREPARATIONS. Cachets, are thin discs of dough of the shape of a soup-plate and varying from in. to 1 in. in diameter. When two of them are placed together with their concave sides toward each other, they form a receptacle in which powders are dispensed. The edges stick together when they are moistened. A somewhat similar method of dispensing is in gelatin capsules, which may be hard or soft, and which are made in different sizes. The hard capsule is used for solids, the soft for liquids. Sometimes the latter contain as much as 15 c.c. ( fl. oz.), but these are difficult to swallow. Cataplasmata, or poultices, are not official preparations now, but are in common use. They are generally made of linseed meal, oatmeal, or bread crumb, which is formed into a paste with hot water, enclosed in thin cotton or linen and applied to the skin. Mustard and other remedies may be added to the poultice in order to induce special effects, and in some cases a poultice consists merely of drugs enclosed in a cloth sack, as in charcoal or spice poultices. Enemata, clysmata, or clysters, are liquid substances injected into the rec- tum for their local or general effects. (See page 31.) CLASSIFICATION OF DRUGS. Vriters on pharmacology and therapeutics arrange drugs on many differ- ent principles. Thus a somewhat antiquated system classifies the vegetable remedies according to the botanical families from which they are obtained, but there is little advantage in this arrangement, for an order may include drugs which differ entirely in their action and in the therapeutic uses to which they are put, while, on the other hand, two widely separated botanical groups may contain identical poisons. Another classification of drugs is according to their therapeutic effects, and this might seem at first sight the most convenient for students of medicine. This plan has its drawbacks, however, for many drugs are used for a large number of different purposes, and it is impossible to describe them under each heading. In addition, the classification in groups is always liable to suggest a much closer resemblance in the effects of the individual drugs than really exists. Thus the drugs often classed as " cardiac stimulants" differ much, not only in their effects on the body in general, but in their action on the heart, and opinions may differ as to whether some of them stimulate or depress the heart. They certainly cannot be substituted for each other in the treatment of heart dis- ease, as is suggested by their being classified together under this heading. Finally, practical therapeutics can be taught only in the clinic, and in the teaching of pharmacology it seems advisable to direct the student's attention rather to the action of drugs than to the practical uses, which can be taught to much greater advantage in connection with the symptoms, prognosis, and other clinical features of disease. The classification of drugs and poisons according to their action on living matter is the natural one, and is based on the same logical principle as the modern classification of plants in bot- any and of animals in zoology. The object is to group together those sub- stances which have most points of resemblance, whether they are obtained from the same or from different orders of plants, and whatever relation they may bear to each other in therapeutics. This classification, which was introduced by Buchheim, has been further developed by Schmiedeberg and his pupils. In the present state of knowledge it is necessarily imper- 42 INTRODUCTION. feet,, and many resemblances and affinities have not gained that recog- nition which they will doubtless receive in the future. Even in its pres- ent imperfect form, however, this classification is the most satisfactory one available, and, unlike the others, it can be easily subjected to such modi- fications as the advance of science renders necessary. If ever the ideal classification be attained, in which the grouping is based upon the chemical reactions of the poisons with the living protoplasm, this natural classification will be found to conform more easily to it than any based upon origin or temporary therapeutic uses. Resemblance in pharmacological action does not necessarily involve simi- larity in chemical composition, as has been already pointed out. But it is found that in many instances the members of a pharmacological group have some general chemical character which distinguishes them from others. Drugs which resemble each other in their pharmacological action, are often used for very different purposes in therapeutics, although this is much less frequently the case now than formerly. This is very generally due to the failure of the clinicians to observe the resemblance in the action of drugs. As they become more familiar with the results of animal experiment, they will recognize that in many instances drugs which they now regard as dis- tinct on account of superficial differences, really resemble each other in all important points, and may be substituted for each other in therapeutics. In this way it is to be hoped that the natural classification of drugs will gradu- ally be found to approach more closely to the therapeutic. At the present time the continued use of the therapeutic classification can only tend to delay this consummation. In this volume, the classification adopted is that of Buchheim and Schmiedeberg, with some slight alterations which seemed to be de- manded by recent progress. The drugs are thrown into a large num- ber of groups which are named from the most prominent member, or from some marked property possessed by all. These groups are ar- ranged, as far as possible, according to their mutual resemblances. It has been found advisable to retain, for the most part, the divisions into organic and inorganic drugs, although this may, perhaps, have to be abandoned in the future. The first series of groups of the organic materia medica are possessed of the common property of inducing more marked local than general effects, and these may therefore be classified in one large subdivision. The second division of the organic drugs is formed of those whose pronounced general action obscures their local effects, when these are not entirely absent. The first few groups of this division are formed of those whose chief action is de- veloped on the central nervous system ; then follow those which in- volve more especially the peripheral nerves, muscles, and secretory or- gans ; these, again, pass into a series in which local irritant action is associated with powerful general effects, and through these into a se- ries of protoplasm poisons. The last series of organic groups consists of those acting chiefly on the heart and vessels directly. The groups of the inorganic drugs show less defined affinities, and are much more difficult to classify than the organic series. The salts of the alkalies and alkaline earths, the acids and alkalies may be thrown into a large and somewhat heterogeneous division, which is easily marked off from that of the heavy metals, which have many points in common in their ef- CLASSIFICATION OF DRUGS. 43 fects in the organism, as in their chemical reactions. The latter divi- sion is led up to by phosphorus and arsenic, and several bodies which it is impossible to classify at present are placed between these and the first inorganic division. Another class is formed of a number of sub- stances which are either present in the normal body, or are merely sub- stitutes for normal secretions, and the final class is composed of a few preparations which are used only for their mechanical effects, and which for the most part are not drugs, although they are included in the pharmacopoeias. It must be emphasized that no attempt is made to draw hard and fast lines of demarcation between the different groups. The essential features of the natural system involve the recognition that this is im- possible. It has therefore been considered best not to indicate any definite point at which the discussion of poisons acting on the central nervous system ends and that of the drugs with peripheral effects be- gins. The student is always liable to lay more importance on such divisions than is intended by the writer, to list those on one side of the dividing line as central, those on the other as peripheral in action, whereas the transition is gradual. The six chief divisions are therefore the only ones indicated. PART I. ORGANIC SUBSTANCES WHICH ARE CHAR- ACTERIZED CHIEFLY BY THEIR LOCAL ACTION. THIS class contains a very considerable part of the drugs included in the pharmacopoeias, although it bears a smaller proportion than for- merly to the other classes. There is still, however, in it a large number of drugs which have practically identical effects, and there is no question that it might be considerably curtailed without loss to therapeutic practice. Many of its members are irritants, and these have been subdivided for convenience into groups according to the organs on which they exert their chief action and the purposes for which they are used in therapeutics, as gastric, intestinal, cutaneous irritants. Others act as protectives, covering injured surfaces (demul- cents, emollients), and still others precipitate the proteids on the sur- faces to which they are applied (astringents). Others seem to act chiefly by affecting the taste, and finally a heterogeneous group which is used in the treatment of intestinal parasites, has been inserted here. I. DEMULCENTS. A large number of colloid substances chiefly gums, dextrins, sugars and starches owe their use in medicine, not to any changes they pro- duce in the cells with which they come in contact, but to the fact that they are cohesive and serve to protect surfaces mechanically. When they are applied to a sensitive surface, they retard the movement of fluid or air against it and thus preserve it from the effects of these agents. This may be illustrated by familiar examples in which the taste of food is altered by their presence, although they have often no taste or odor in themselves. Sugar dissolved in mucilage tastes less sweet than in water, and acids are also less appreciated, as may be ob- served in many fruits. For example, the raspberry contains more acid and less sugar than the currant, but in the former the acid taste is con- cealed by the presence of large quantities of colloids, so that the rasp- berry is regarded as a sweet fruit, the currant as an acid one. Even cold is felt less when a colloid substance is present in the fluid swal- lowed ; thus, ice-cream or iced milk does not feel so cold on the tongue and throat as frozen water, because the colloid proteid substances form a protecting layer over the surface, and prevent the cold mass from reaching the sensory terminations so freely as it otherwise would. A 45 46 ORGANIC SUBSTANCES ACTING LOCALLY. number of experiments carried out by Tappeiner 1 show that other organs may be protected in the same way by colloid solutions. Strong salt solution applied to a motor nerve first stimulates and then slowly paralyzes it, but Tappeiner found that both of these effects are much Jess marked if the solution be made up with mucilage instead of with water, because the salt does not reach the nerve so readily. In the same way, intense pain is caused in a wound by strong salt solution, but is much less severe if the solution contain colloid material. When demulcents reach the stomach, they appear to coat the wall and thus to alter the sensation arising from food, for Quincke found in a case of gastric fistula that the patient could distinguish milk from water even when it was passed directly into the stomach, and Pawlow states that the presence of starch in the stomach alters the secretion induced by food. Tappeiner found that much less inflammation of the intestine is caused by irritants if they are suspended in demulcents than if they are dissolved in water ; at the same time the presence of colloid unabsorbable bodies may increase the efficiency of purgatives by pre- venting their absorption in the upper part of the bowel. The digestion of proteids outside the body is retarded by the presence of the demul- cents, and probably this is also true of the process in the stomach. Colloid bodies also retard the absorption of fluids from the stomach and bowel, and this leads to a feeling of distention, which is much less marked if the same amount of fluid be swallowed without colloid ; for instance, water is absorbed more rapidly than milk or beer. The slow absorption of colloid fluids allows time for decomposition, and this may give rise to irritation and catarrh. The colloids them- selves are absorbed very slowly, and probably only in a condition of semi-decomposition. After absorption, they are oxidized in the tissues and therefore act as foods to some extent, although their slow absorp- tion prevents their being of much value. They have, of course, no effect as demulcents after absorption, but the large quantity of fluid with which they are generally taken may be of benefit in some condi- tions. Demulcents are used to cover inflamed surfaces ; in tonsillitis, for example, they may be applied as gargles, or better by sucking lozenges containing them. They are not often applied externally for this pur- pose, as they are liable to serve as media for the growth of micro- organisms. In gastric and intestinal catarrh their use is objectionable for the same reason, their slow absorption leading to decomposition with the formation of irritants, which may do more harm than is coun- terbalanced by their protective action. Instead of demulcents, some of the oils, such as olive oil (p. 51), have been recommended as pro- tectives in disease of the stomach and intestine. In acute irritant poisoning the demulcents are often of great value, as they protect the stomach wall from the effects of the poison. The best remedy in these cases, because the most readily obtainable, is milk or white of eggs. 1 Tappeiner, Archives internat. d. Pharmacodyn., x., p. 67. DEMULCENTS. 47 Their effects in retarding the absorption of other remedies may be taken advantage of. Thus when the effect of alcohol on the stomach or bowel is desired, it is given as wine, which contains colloid material, and is therefore, absorbed slowly ; it must be noted, however, that these same colloids delay digestion much more than alcohol itself. In the same way opium and extract of nux vomica are prescribed when the local action on the bowel and stomach is desired, while the pure alkaloids, morphine and strychnine, are administered for their effects after absorption. Demulcents are often given instead of pure water in cases where it is desired to administer large quantities of fluid, as they have more " body " and are more agreeable to the taste. Thus, barley water or some other demulcent may be advised in order to assuage the thirst of fever, or to dilute the urine when it is too concentrated or too acid. Demulcents are often used as the basis of enemata which are intended to be absorbed, because solutions containing colloids are less irritant and therefore less liable to set up peristalsis than pure water. For this purpose starch solution is generally used. Some of the gums, notably acacia and tragacanth, are seldom advised as demulcents, but are often prescribed in order to hold in suspension in water such insoluble bodies as resins and oils, or to give cohesion to pills and lozenges. PREPARATIONS. Acacia (U. S. P.) Acaciae Gummi (B. P.) (gum arable), a gummy exuda- tion obtained from Acacia Senegal, consists of the potassium, magnesium, and calcium salts of a weakly acid substance, arabin or arabinic acid (C 6 H 10 O 5 ). It is soluble in equal parts of water, and is used as a demulcent, but more largely as a vehicle for other drugs. MUCILAGO ACACIA (U. S. P., B. P.). About 1 part acacia in 2 of water. Dose, 16 c.c. (4fl. drs.). Syrupus Acacice (U. S. P.). Tragacantha (U. S. P., B. P.), a gummy exudation from various species of Astragalus, contains salts of arabin and tragacanthin. Tragacanthin differs from arabin in not dissolving, but merely swelling up into a jelly in water. Tragacanth is used chiefly to suspend heavy powders in water. MUCILAGO TRAGACANTH^E (U. S. P., B. P.), formed of tragacanth, glycerin and water. In the B. P. alcohol is used instead of glycerin. Dose, 16 c.c. (4 fl. drs.). Glycerinum Tragacanthse (B. P.), a solution of tragacanth in^ glycerin and water. Pulvis Tragacanthse Compositus (B. P.), contains tragacanth, gum acacia, starch and sugar. Dose, 20-60 grs. Sassafras Medulla (U. S. P.), the pith of Sassafras variifolium (sassafras)o Ulmus (U. S. P.), the inner bark of Ulmus fulva (slippery elm). Althaea (U. S. P.), the root of Althaea officinalis (marsh-mallow). Linum (U. S. P., B. P.), the seed of Linum usitatissimum (linseed). Linum Contusum (B. P.), crushed linseed. Mucilago Sassafras Medulla (U. S. P.). Dose, 16 c.c. (4 fl. drs.). Mucilago Ulmi (U. S. P.). Dose, 16 c.c. (4 fl. drs.). These all contain colloid substances which are extracted with hot water, and which are believed to be nearly related to arabin. They are largely used in 48 ORGANIC SUBSTANCES ACTING LOCALLY. domestic medicine as demulcents in sore throat, and may be prescribed to sus- pend powders or oils. The syrup of marsh-mallow is a pleasant flavor. Triticum (U. S. P.), the rhizome of Agropyrum repens, or couch-grass, contains mannite, laBvulose, and a starchy substance, triticin. Its decoction is used as a beverage in fever, and to dilute the urine. It has a certain popular reputation as a diuretic in suppression of the urine, calculus, etc. , but this is entirely unmerited, for it increases the urine simply by the water given with it. Amylum (U. S. P., B. P.), or starch, may be formed into a jelly by boiling in water, and may then be used for the same purpose as the demulcents. Glyceritum Amyli (U. S. P.), Glycerinum, Amyli (B. P.), is a jelly formed by heating starch with water and glycerin. Amygdala Dulcis (U. S. P., B. P.), or sweet almonds, the seed of Prunus amygdala dulcis, contains a fixed oil and emulsin, a ferment, but, unlike the bitter almond, no amygdalin. When triturated with water it forms an emulsion, or mixture, which is bland and demulcent. Emulsum Amygdala (U. S. P.), Mistura Amygdala (B. P.). Dose, 120 c.c. . (4 fl. oz.). Pulvis Amygdalse Compositus (B. P.) contains sugar and acacia with almond. Syrupus Amygdalae (U. S. P.) is formed from a mixture of sweet and bitter almonds, and therefore contains a small proportion of prussic acid, but may be used in the same way as the demulcents with perfect safety. Glycyrrhiza (U. S. P.), Glycyrrhizae Radix (B. P.), or liquorice-root, the root of Glycyrrhiza glabra (var. glandulifera), is used as a demulcent, and more largely to flavor medicines. It has a pleasant, sweet taste, owing to the presence of Glycyrrhizin, an acid glucoside, which is combined with calcium and ammonia in the plant, and is not soluble in cold water, but swells up in it to a jelly-like mass. Glycyrrhizin is probably decomposed in the body ; the urine is often found to contain a reducing body after the admin- istration of liquorice. EXTRACTUM GLYCYRRHIZA (U. S. P.. B. P.). Dose, 1 G. (15 grs.). Extractum Glycyrrhizce Purum (U. S. P.). Dose, 1 G. (15 grs.). Fluidextractum Glycyrrhizce (U. S. P.), Extractum Glycyrrhizce Liquidum (B. P.). Dose, 2 c.c. (30 mins.). Glycyrrhizinum Ammoniatum (U. S. P.), the ammonium salt of glycyrrhizin. PULVIS GLYCYRRHIZA COMPOSITUS (U. S. P., B. P.) contains senna. Dose, 2-8 G. (30-120 grs.). TROCHISCI GLYCYRRHIZA ET OPII (U. S. P.). MISTURA GLYCYRRHIZAE COMPOSITA (U. S. P.), " Brown Mixture," con- tains opium, antimony and spirits of nitrous ether. Dose, 15-30 c.c. (1-2 tablespoonfuls). The extract is largely used in the form of lozenges for its demulcent ac- tion, and is very frequently used to make up pills. It is slightly laxative, and may be used as a pleasant aperient for children ; the compound powder is more reliable for this purpose owing to its containing senna, one of the vegetable purgatives. The lozenges and the brown mixture contain opium and are used largely in cough and in catarrh of the air passages. Numbers of other substances are used as demulcents in domestic medi- cine, and are found in different pharmacopoeias. Examples of these are barley (Hordeum), salep, verbascum and quince seeds. Iceland moss is a lichen (Cetraria islandica), and contains starch bodies together with acids, which can be removed by soaking in dilute alkaline solutions for some time. Chondrus (U. S. P.) (Irish moss or Carragheen), Chondrus crispus, a seaweed gathered on the coasts of Ireland and Massachusetts. Chondrus contains a carbohydrate, carrageenin. The decoction forms a jelly when cold, and was formerly supposed to form a valuable food in illness, but it is of little value for this purpose, for only about ^V'sV of the jelly is solid matter, the rest water. EMOLLIENTS. 49 II. EMOLLIENTS. Emollients are bland, oily substances which are applied to the skin to protect it from irritation, and to render it softer and more elastic, and thus bear the same relation to the skin as the demulcents to the mucous membranes. Their effect in rendering the skin softer and more pliable may be due in part to their penetration into the surface layers, but may also be explained by the slight congestion induced by the rubbing and massage used in their application. The older emollients were chiefly animal and vegetable fats and oils, but several newer drugs of this class are derived from petroleum. The effects of these drugs when applied to the skin are purely local. No doubt some small percentage is absorbed into the tissues, but this has no known effect in man, and although the fats and oils are valu- able foods when taken internally, this plays no part in their effects when applied to the skin. The emollient preparations promote the absorption of drugs dis- solved in them, because they mix readily with the thin layer of oily sebaceous matter which covers the epithelium. The active substances dissolved in them therefore come into intimate contact with the absorb- ing cells lining the ducts of the glands, while watery solutions are separated from the lining cells by a layer of sebum. If this layer be dissolved off by alcohol, watery solutions are also absorbed rapidly, and alcoholic solutions are absorbed as quickly as oily solutions, be- cause the alcohol is miscible with the sebum. On the other hand solutions in water come into more intimate contact with the cells of the mucous membranes and with the subcutaneous tissues, and are there- fore more readily absorbed by these than oily solutions. To ensure rapid absorption, a drug should be dissolved in some emollient if it is to be absorbed by the skin, in water when it is to be administered internally or hypodermically. Solutions in oil of such antiseptics as carbolic acid are much less powerful than those in water, because car- bolic acid being more soluble in oil fails to diffuse into the watery proto- plasm of the microbe, for which it has less affinity. (See Antiseptics of the Benzol Series.) But antiseptics which are more soluble in water than in oils are said to be equally active in both solvents. The emollients are applied as protectives in abrasions, cuts, bruises, chapped hands, burns ; they are less often used alone in extensive skin diseases, but are usually prescribed in these as the basis of ointments in which other remedies are incorporated. There is no question that the protection afforded to the part and the exclusion of the air by the oily emollient plays an important part in the action of these reme- dies, and it seems probable that in many cases equally good results would follow the application of the emollient without any active ingredient. 50 ORGANIC SUBSTANCES ACTING LOCALLY. PREPARATIONS. Adeps (U. S. P., B. P.), lard ; the prepared internal fat of the abdomen of the pig, purified by washing in water, melting and straining. Adeps Benzoinatus (U. S. P.), Adeps Benzoatus (B. P.), benzoinated lard, is prepared from lard by the addition of benzoin, which is slightly antiseptic and preserves it from becoming rancid, UNGUENTUM (U. S. P.), ointment, is a mixture of lard and yellow wax. It was formerly known as Unguentum Simplex, and is the basis of many other ointments. Unguentum Diachylon (U. S. P.) is formed from lead plaster and olive oil, perfumed with oil of lavender. The lead is inert, the action being identical with that of ordinary ointment. UNGUENTUM AQU^: Ros^: (U. S. P., B. P.), cold cream, is formed of sper- maceti, white wax, oil of almonds, and some borax, scented with rose water. Sevum Praeparatum (U. S. P., B. P.), mutton suet, is obtained from the abdominal fat of the sheep. Lard and suet have the ordinary constituents of animal fats, stearin, pal- mitin- and olein. They are seldom used alone, but form the basis of numer- ous ointments. These animal fats tend to putrefy, and are then rendered irritant by the presence of free acids (rancidity), and have therefore been replaced to a considerable extent of late years by other preparations which do not suffer from this drawback. Adeps Lanae Hydrosus (U. S. P., B. P.), hydrous wool-fat, lanolin, the purified fat of sheep-wool, mixed with not more than 30 per cent, of water. Adeps Lance (U. S. P., B. P.), wool-fat without water. Lanolin has been used extensively in medicine only in the last few years. It consists of cholesterin esters with some impurities, does not become ran- cid, and differs from the older fats also in being miscible in twice its weight of water without losing its ointment consistency. Lanolin is very often used as an emollient application, as well as to form a basis for more active drugs. Other preparations of wool-fats are known as lanichol and alapurin. Petrolates or Paraffins. When the more volatile constituents of petroleum are distilled off, there remain a number of higher hydrocarbons, chiefly of the marsh gas series, which are used in medicine as emollients. The lower of these hydrocarbons are fluid at ordinary temperatures and are known as Petrolatum Liquidum (U. S. P.), Paraffinum Liquidum (B. P.), a colorless, oily transparent liquid without odor or taste. When these are removed there remains PETROLATUM (U. S. P.) and PETROLATUM ALBUM (U. S. P.), PARAFFINUM MOLLE (B. P.), soft petrolate, vaselin, which has the consistency of an oint- ment, is yellow or white in color, and is liquefied a few degrees above the tem- perature of the blood. When the distillation is carried further, the residue is solid at ordinary temperatures, and is known as Paraffinum (U. S. P.), Paraffinum Durum (B. P.), or hard paraffin, which melts at a somewhat higher temperature than vaselin. Unguentum Paraffini (B. P.) is a mixture of three parts of hard paraffin with seven parts of vaselin. By mixing the petrolates a salve of any desired consistency may be ob- tained. Soft petrolate is often known as petrolatum, as it is much more extensively used than the others. It is used as an emollient, and as a basis for ointments and has the advantage over the older lard and suet that it does not become rancid. Liquid vaselin has been used to dissolve irritant substances for subcutaneous injection, as much less pain is caused when they are dissolved in vaselin than when water is used. Sobieranski l has shown that vaselin rubbed into the skin is absorbed to some extent, and may be recovered from the muscles and to a less extent from other organs, Babbits 329 f ^ J_l_HAOV^J.\^0 C4-J.AV1. UVy C* AV^OQ V^A.WU.11 J.AV/JJJ. ' 1 Arch. f. exp. Path. u. Pharm., xxxi., p. EMOLLIENTS. 51 lost flesh and some of them died under the continued application of vaselin, but this may have been due to the manipulation and not to the drug itself. Several Oils are also used as emollients. Oleum Olivse (U. S. P., B. P.), olive oil, a fixed oil obtained from the ripe fruit of the olive, Olea europsea. Oleum Lini (U. S. P., B. P.), Linseed or Flaxseed oil. Oleum Amygdalss Expressum (U. S. P.), Oleum Amygdalae (B. P.), a fixed oil expressed from bitter or sweet almonds. It is to be distinguished from the volatile oil obtained from the bitter almonds. The fixed oil contains no prussic acid. Oleum Gossypii Seminis (U. S. P.), Cotton-seed oil. Oleum Adipis (U. S. P.), oil of lard. These all resemble each other in their composition, and may be used as emollients. Olive oil is generally preferred to the others, but is much more expensive, and it is probable that much of the so-called olive oil is really purified cotton-seed oil. Olive oil has been advised as a cholagogue, but has been shown by more exact methods of research to have no effect whatever on the secretion of the bile. It sometimes gives relief in biliary colic and dys- entery and in some gastric disorders accompanied by pyloric spasm, probably from its acting as a protective to the mucous membrane of the stomach and duo- denum. A wineglassful is given two or three times a day before meals ; in these large doses it possesses a high food- value. 1 Cera Flava (U. S. P., B. P.), yellow wax. Cera Alba (U. S. P., B. P.), white wax prepared from the yellow by bleaching. Cetaceum (U. S. P., B. P.), spermaceti, obtained from the cachelot (Phys- eter macrocephalus), one of the \vhales. These three preparations are not used alone, but are often added to the emollients and ointments in order to give them a firmer consistency, which is especially desirable in hot climates and in summer. Ceratum (U. S. P.) a mixture of 3 parts of wax with 7 of lard. Unyuentum Cetacei (B. P. ) is a mixture of white wax and spermaceti and olive or almond oil. GLYCERIXUM (U. S. P., B. P.), Glycerin, a liquid obtained by the decom- position of animal or vegetable fats or fixed oils, and containing not less than 95 per cent, of absolute glycerin, C 3 H 5 (OH) 3 ; clear, colorless, of a syrupy consistence, oily to the touch, with a sweet taste and no odor, soluble in water and alcohol. Glyceritum Amyll (U. S. P.), Glycerinum Amyli (B. P.), glycerite of starch. Glyceritum Vitelli (U. S. P.), glyconin, glycerite of yolk of eggs, may be used as a protective, but is more largely prescribed to form emulsions. Glycerin is used as a solvent for a number of other drugs, the prepara- tions being known as glycerites (U. S. P.), glycerines (B. P.). Glycerin is somewhat irritant to the unbroken skin, when it is ap- plied in the pure form, and even diluted glycerin causes pain and smarting when it is applied to unprotected surfaces such as cuts or burns, but the pain soon disappears, and glycerin then acts as a pro- tective. The irritation is due to the glycerin abstracting the fluids of the tissues owing to its avidity for water. Glycerin and its prepara- tions are used very extensively as applications to slight wounds, in ir- ritation of the skin and lips from exposure to cold, and in similar con- ditions. They are often applied to hard, dry crusts on the skin in order to soften them and permit of their removal. 1 Cohnheim, Ztschr. f. klin. Me.d, lii., p. 110. 52 ORGANIC SUBSTANCES ACTING LOYALLY. The irritant action of glycerin causes peristalsis and evacuation of the bowels when small quantities are injected into the rectum ; the stool is of almost ordinary consistency, and no pain or colic is felt subsequently, nor does the remedy cause more than one evacuation. Glycerin may be injected into the rectum for this purpose (dose 2-5 c.c., J-l teaspoonful), but a more convenient form is the glycerin supposi- tories, Suppositoria Glycerin!, which are made up with stearic acid and sodium carbonate, U. S. P., with gelatin, B. P. These suppositories are found not to keep well, as the glycerin tends to attract moisture and then escapes ; to avoid this they are often encased in paraffin, which is broken off immediately before they are inserted. Glycerin sup- positories are used in constipation instead of the ordinary aperients, and they have also been advised in parturition to increase the pains. Large doses of glycerin taken internally sometimes cause purgation, but it is not a reliable remedy when administered in this way. Glycerin in large quantities is poisonous whether it is taken by the mouth or injected hypodermically or intravenously. It is true that no case of glycerin poisoning in man is known, but large doses are fatal to animals in the course of a few hours. The chief symptoms are restlessness, agitation, acceleration of the heart and respiration, general weakness, tremor and convulsions, which finally end in somnolence, coma, and death from failure of the respiration. The convulsions are marked only after large doses, when they may assume a tetanic character. A rise in the temperature has been noted by several observers, followed by a fall which continues until death. When glycerin is injected subcutaneously in large quantities, haemoglobin appears in the urine, while this is rarer when it is given by the mouth, and scarcely ever occurs after intravenous injection. This is ob- viously due to the destruction of the red blood cells, but glycerin added to the drawn blood does not act so strongly on it as many other bodies which cause no hsemoglobinuria. Filehne explains the appearance of haemoglobin in the urine after the subcutaneous injection of glycerin by supposing that the glycerin remains outside the vessels for some time, and withdraws the fluid from the red cells as they pass through the poisoned zone. As the cells return into the larger vessels, they take up fluid again and give off hemoglobin. On the other hand, when glycerin is injected into the blood, it diffuses rapidly all over the body, and the blood cells are less acted on by the diluted poison and do not alternately shrink and swell in size. In addition to its action on the blood cells, glycerin apparently acts directly on the central nervous system, as is shown by the violent convulsions. Glomerulonephritis has also been observed in animals. Glycerin is absorbed rapidly from the intestine, and undergoes combustion in the tissues, only a very small fraction of it reap- pearing in the urine. Some authors describe a reducing substance in the urine after the ingestion of glycerin, but this has not been confirmed on more careful investigation. It follows from the fact that glycerin is oxidized in the tissues that ifc must supply the body with energy and act in some sense as a food. This is of interest chiefly because, the ordinary fats being compounds of glycerin, a certain amount must be contained in the food, but it is also of some thera- peutic importance, because glycerin has been advised as a food in inanition, and has even been said to rival cod-liver oil. In respect to its value as a food, glycerin resembles ordinary alcohol, being readily absorbed, and un- doubtedly increasing the total energy of the body. But it is still undecided EMOLLIENTS. 53 how far it leads to an economy of the nitrogenous tissues, as the fats and carbohydrates do. Its combustion saves a certain amount of the fat of the body from being destroyed, but glycerin tends to increase the non-nitrogen- ous, and not the nitrogenous reserve of the body, and is therefore of only secondary importance as a food, although, like alcohol, it may be of value under certain conditions. Glycerin has been said to have some effect on the sugar formation in the tissues. In some forms of experimental glycosuria, apparently less sugar is found in the urine if glycerin be administered, and in a certain number of cases of diabetes in the human subject, some improvement is said to have occurred under glycerin treatment. No satisfactory explanation of this point has been offered. Quite apart from its supposed action on diabetes, glycerin has been used as a substitute for sugar in this disease, but its place has been taken of late years by saccharin. Glycerin has been shown to possess some virtue as an antiseptic, probably from its withdrawing water from the microbes, but like the oils (page 48) it is a less suitable solvent for many antiseptics than water. BIBLIOGRAPHY OF GLYCEEIN. Dujardin-Beaumetz and Audiye. Bull, de Therap., xci., p. 51. Plosz. Pfliiger's Arch., xvi., p. 153. Ransom. Journ. of Phys., viii., p. 99. Schwahn. Eckhard's Beitrage zur Anatomie und Physiolog., viii., p. 167. Filehne. Virchow's Arch., cxvii., p. 413. Munk. Virchow's Arch., Ixxvi., p. 119 ; Pfluger's Arch., xlvi., p. 303. Arnschink. Zeitschr. f. Biol., xxiii., p. 413. Christomanos. Virchow's Arch., clvi., p. 582. Wunschheim. Arch. f. Hygiene, xxxix, p. 101. Along with the emollients, or oily protectives, may be mentioned another class of mechanical agents, the Dusting Powders. Any dry, insoluble, fine powder applied to irritated surfaces of the skin, or slight abrasions, will protect these from the air, and from contact with the clothes and other sources of pressure. These powders, at the same time, soak up any secretions, and render the injured spot less liable to bacterial infection, as they form a more or less impermeable crust. Powders used for this purpose should not be absorbed, or, if absorb- able, should not induce any toxic effects. Those most commonly em- ployed are the phosphate and carbonate of lime, talc (Talcum, Talcum Purificatum, U. S. P.), (magnesium silicate), fullers' earth and kaolin (aluminum silicates), starch, and Lycopodium (U. S. P.), which con- sists of the spores of Lycopodium clavatum (club moss). A large number of powders are used as surgical dressings, most of them being credited with more or less antiseptic power. In many in- stances, however, their antiseptic action is so slight that it would ap- pear that most of their virtues are due to their mechanical properties, and not to their bactericidal action. 54 ORGANIC SUBSTANCES ACTING LOCALLY. III. SUGARS AND FLAVORING SUBSTANCES. Sugars are used in medicine chiefly to disguise preparations of un- pleasant taste, and in the small quantities usually employed have little further effect. In large quantities sugars, like other diffusible bodies, act as irritants to the stomach and bowel, and comparatively small quantities of some sugar substances possess an aperient action. Thus molasses and imperfectly refined sugar have some reputation in do- mestic medicine as aperients, and honey, manna, Cassia fistula, and several fruits are included as mild laxatives in the pharmacopoeias. They are scarcely prescribed alone in medicine, but are used to give bulk to preparations of the stronger purgatives, such as senna. Their aperient action seems to be due to their colloid form, as pure sugar has no such effect, and it is possible that they merely delay the absorption of fluid, and thus cause softer evacuations than would otherwise occur. PREPARATIONS. Saccharum (U. S. P.), Saccharum Purification (B. P.), cane sugar. SYRUPUS (U. S. P., B. P.), a concentrated solution of sugar. Syrup is the basis of a large number of medicated, syrups of the pharmacopoeias. Sugar and syrup are used exclusively to sweeten mixtures and to aid in the suspen- sion of insoluble bodies. In place of ordinary syrup many of the flavored prep- arations may be used, such as syrup of citric acid, of acacia, of almonds, etc. Saccharum Lactis (U. S. P., B. P.), sugar of milk, lactose, is not so sweet as ordinary sugar, and is much less liable to deliquesce, so that it is used largely to give bulk to powders. It has been said to have diuretic properties when given with large quantities of water, and to cause purgation when given in a more concentrated solution. Asses' milk contains more lactose than cows' milk, and has been recommended for its slight aperient action in chronic constipation. Maltum (U. S. P.), malt, barley grain partially germinated and then dried. Extractum Haiti (U. S. P.). Dose, 16 c.c. (4 fl. drs.). Mel, honey, and Mel Depuratum (U. S. P., B. P. ), or clarified honey, are used to give taste to mixtures, and have a very slight aperient action, so that they may be advised as articles of diet in habitual constipation. Some medicated honeys are used, of which Mel ROSCR is included in the U. S. P. , Mel Boracis in the B. P. Oxymel (B. P.) is a mixture of honey and acetic acid. Dose, 12 fl. drs. Syrupus Glucosi (B. P.), a mixture of liquid glucose and syrup. Manna (U. S. P.), a saccharine exudation of Fraxinus ornus (Flowering Ash), contains about 50-75 per cent, of mannite, C 6 H H (OH) 6 , a hexatomic alcohol of sweetish, sugary taste. It has slight aperient properties when taken in large quantities. Cassia Fistula (U. S. P.), purging Cassia, the fruit of Cassia fistula. The pulp, Cassiae Pulpa (B. P.), contains considerable quantities of sugar. Tamarindus (U. S. P., B. P.), tamarinds ; Ficus (U. S. P., B. P.), figs ; Prunum (U. S P., B. P.), prunes, all contain sugar in considerable quantity. These are used as mild aperients and flavoring agents, generally in combi- nation with more powerful remedies. Thus manna is used in Infusum Sennse Co. (U. S. P.), and the others form ingredients of Confectio Sennse. They are not prescribed alone, but the fruits may be advised as articles of diet where a mild laxative is required. The tamarind pulp may owe its aperient action in part to the presence of tartrates, citrates, malates and other cathartic salts. (See Saline Cathartics.) SIMPLE BITTERS. 55 Frequently other flavors are preferred to sugar, which is especially disliked in fever cases, as sweet fluids do not quench the thirst so eifect- ually as acids and bitters. Many of the preparations of the volatile oils and some of the demulcents are used almost exclusively as flavor- ing agents, and in some both sugar and volatile oil are combined, as in the syrups. Instead of sugar some artificial compounds have been introduced of late years. Glusidum (B. P.), Benzosulphinidum (U. S. P.), or Saccharin, C 6 H, \ gQ )> NH, and its sodium salt, C 6 H 4 \ ^ / N Na, or soluble saccharin, are the best known of these. Saccharin is a light, white crystalline powder, soluble in 400 parts of water and in 25 parts of alcohol. It is about 500 times as sweet as sugar, and gives a distinct flavor to 70,000 times its weight of water. Dulcin, another aromatic compound, is said to be even sweeter than saccharin. None of these tastes exactly like sugar, however, there being a distinct flavor besides that of sweetness, and patients generally object to them after a short time. They have been used as substitutes for sugar in diabetes, a dis- ease in which sugar is to be avoided as far as possible. Some writers state that in the presence of saccharin the digestive ferments act more slowly than usual, but the retardation is only trifling and does not preclude the use of saccharin in the small quantities necessary to sweeten the food. Like the other derivatives of benzol, saccharin has some anti- septic action and tends to lessen the putrefaction of the intestinal con- tents. Even very large doses of saccharin may be injected intrave- nously in animals without other effect than some depression and stupor. Some pharmacopceial preparations are designed to give color to solutions, but are seldom or never prescribed, although they are sometimes added by the pharmacist. Coccus (U. S. P., B. P.), cochineal, the dried female of Coccus Cacti. Tinctura Cocci (B. P.). Crocus (B. P.), saffron. Tinctura Croci (B. P.). Santalum Rubrum (U. S. P.), Pterocarpi Lignum (B. P.), red sanders, saunders or sandal wood. Rhceados Petala (B. P.), the fresh petals of Papaver Rhceas, red poppy. Syrupus Rhoeados (B. P.), i-1 fl. dr. Poppy petals contain none of the alkaloids of opium. IV. SIMPLE BITTERS. This group includes a number of substances which have little in common except their bitter taste and their comparative inactivity in the body. Several alkaloids may be placed in it, Berberine, Buxine, Menispermine and Canadine, for, although these are poisonous in very large quantities, they are harmless in those in which they are contained in the preparations used in therapeutics. In addition to these there may be placed in it numerous neutral bodies, possessing an intensely bitter taste, but with little or no further action, such as the Quassiins, Columbin, and a few weak acids and glucosides. 56 ORGANIC SUBSTANCES ACTING LOCALLY. Pharmacological Action. These substances, or rather the prepara- tions containing them, are largely used in therapeutics in order to in- crease the appetite, and their administration is often followed by a dis- tinct improvement in the digestion and an increase in weight. Alimentary Tract. The explanation of these effects is still obscure, although a large number of investigations have been made as to their effects in the stomach. In experiments with artificial digestion the pure, principles have generally been found without influence on the ac- tivity of both gastric and pancreatic fluids, the slight variations ob- served lying within the limits of error ; and where any distinct effect has been observed, it has generally been a retardation of the process. The ordinary therapeutic preparations, on the other hand, generally delay artificial digestion, owing to the presence of tannic acid and colloid substances. The bitters neither destroy nor greatly retard the growth of bacteria in culture media, and most of them seem to be without ef- fect on the yeast fermentation of sugar solutions, although Vas found that quassiin retarded it somewhat. The absorption from the stomach is unchanged by the presence of bitters. In regard to the effect of the bitters on the secretion of the stomach, Reichmann states that in man the bitters taken during gastric digestion do not affect the secretion, although they seem to retard the proteolysis. When bitters are taken on .an empty stomach, less gastric juice is secreted immediately than if the same amount of water had been swal- lowed, but some time afterwards a very active secretion occurs. '/Reich- mann, therefore, advises the bitters in cases of insufficient acidity of the astric juice, the remedy to be taken half an hour before meals. yOn the other hand, in hyperacidity the bitters may aggravate the condi- tion. This statement is in accordance with the observations of Bokai, that the secretory cells of the peptic glands present the histological ) appearances of activity after the bitters have been ingested. In animal experiments, the movements of the stomach are said to be somewhat augmented by the bitters, and poisonous doses of several of them increase the movements of both stomach and bowel, and cause considerable hypersemia. But it is unknown whether this action is QT/ common to all the bitters, and whether the small quantities used in ther- v y apeutics cause any increase in the blood supply. According to Reich- / mann, the movements are probably somewhat less than usual in man. | Pohl found that bitters given by the stomach increase to a marked /extent the leucocytes in the blood of the dog, and Ramm has shown I that this holds true for man, and adds that the red blood-cells are also augmented. The secretions of the pancreas and the bile are unaffected Iby the bitters, but intestinal secretion and absorption are increased an f hour after bitters reach the intestine (Jodlbauer). In the mouth the bitters cause a reflex flow of saliva, and it has been suggested that this may in part explain their therapeutic effect. Large quantities are said to cause a burning sensation in the oasophagus and stomach. The whole literature on the action of the bitters is full of contradic- tions, which is perhaps to be explained by the fact that comparatively SIMPLE BITTERS. 57 few investigators have examined their effect in human digestion, and many have contented themselves with the results of intravenous injec- tion in animals. The most probable explanation is that of Reichmann, that the gastric secretion is increased. It may be suggested here that this does not involve a direct action on the secretory epithelium, for I Pawlow and his pupils have shown that the chief factor that deter - I mines the activity of the gastric secretory cells is the odor and taste of I the food. In dogs with gastric fistulse, in which the food swallowed did not pass into the stomach but escaped through a wound in the resophagus, the taste and odor of food caused a profuse reflex secretion of gastric juice, and bitters given shortly before augmented this reflex (Borissow). It is quite possible that bitter tastes may cause this reflex secretion in man, and that the whole effect may be explained by the one property common to all these drugs their bitter taste. In addi- tion, it is to be remembered that the improvement is largely subjective, and that the bitters are capable of producing a considerable impression upon patients, so that the effects may be due in part to suggestion and not to any real action of the drug. Action after Absorption. In very large quantities some of the bitters produce effects that are obviously due to their absorption. These have seldom been observed in man, but have been studied in animal experiments. Thus Compardon states that in many individuals 0.12 G. of quassiin produces burning in the throat and stomach, discomfort, headache, nausea, and vomiting. In flies and other insects it has a narcotic action. Columbin and cetrarin were found by Kohler to increase the blood pressure by stimulation of the vasomotor centre when they were injected intravenously. Ramm states that the intravenous injection of cetrarin causes irritation of the stomach and bowel, purging and vomiting, and general paralysis of the central nervous system, which is preceded by convulsions in mammals. He did not observe any increase in the blood pressure. Both the glucosides of condurango produce in dogs ataxia and loss of coordination, with increased movement, and eventually convulsions, and death follows in 12-72 hours or longer. The brain seems the part chiefly affected in mammals, although the reflex excitability of the spinal cord is also augmented in the frog (Jukna). Buxine possesses considerable antiseptic power, and prevents the movement of leucocytes and of the lower organisms in the same way as quinine. Large doses often cause vomiting, confusion, giddiness and tremor, with diarrhoea in dogs, but are sometimes without effect. Aristolochine, which has been found in several species of Aristolochia, and probably occurs in the official serpentary, produces in rabbits acute necrotic nephritis, with albuminuria and ursemic symptoms. In dogs it causes a very marked fall of blood pres- sure, and hemorrhages in the intestinal mucous membrane, but no nephritis. The poisonous action of aristolochine is very similar to, but much more powerful than that of aloin (Pohl). Lupulinic acid obtained from hops, when injected as a neutral salt into the blood, causes first stimulation and then paralysis of the medullary centres, but has very little effect when given by the stomach even in large doses (Dreser). In beer an oxidized product of lupulinic acid occurs, which has no effect even when injected into the blood. Berberlne is a very widely distributed alkaloid of the pyridine series (C 20 H 17 NO 4 ), and when administered in very large quantities per os, causes diarrhoea, and occasionally vomiting, tremor, acceleration of the pulse and respiration and general weakness, from which the animal recovers only slowly. Its subcutaneous or intravenous injection is followed by the same 58 ORGANIC SUBSTANCES ACTING LOCALLY. symptoms, but paralysis of the hind extremities, convulsions, and asphyxia from failure of the respiratory centre may occur when it is administered in this way, while the largest quantities are not fatal when exhibited by the stomach. The acceleration of the pulse seems due to paralysis of the inhibi- tory terminations in the heart, and is accompanied by a fall of blood pres- sure from the effects of the alkaloid on the vasomotor centre and on the heart directly. Berberine has been credited with causing contraction of the uterus and of the spleen, but this is disputed. It has also been said to resemble quinine in its effects on bacteria and on the leucocytes, but only in very strong solution. Berberine seems to be excreted in part by the kidney unchanged, and is said to cause nephritis in large doses. The cotoin of Goto bark, and the paracotoin and other constituents of Paracoto bark are said to cause dilatation of the intestinal vessels when they are injected intravenously or perfused through the mesenteric vessels. Para- cotoin is much weaker than cotoin. Orexine (C 14 H 12 N 2 ), an artificial base, seems to stand midway between the peppers and the bitters in its action, as it is somewhat more irritating than most of the latter. Injected into the frog it induces paralysis, which is ap- parently of peripheral origin, and its subcutaneous application in mammals is followed by tremor, tonic and clonic convulsions, dyspnoea, acceleration of the heart and vomiting. It has some antiseptic action, and tends to form methsemoglobin when mixed with the blood. No symptoms have been ob- served from its use in man, except increased appetite and augmentation of the gastric secretion, and in a few cases a feeling of heat in the throat and some nausea. PREPARATIONS. Gentiana (U. S. P.), Gentianse Radix (B. P.), gentian, the root of Genti- ana lutea, contains a glucoside, gentiopicrin, a neutral body, gentisin, and a trace of tannic acid. 1 G. (15 grs.). EXTRACTUM GENTIANS (U. S. P., B. P.), 0.1-0.5 G. (2-10 grs.). Fluidextractum Gentiance (U. S. P.), 0.5-2 c.c. (10-30 mins.). TINCTURA GENTIANS COMPOSITA (U. S. P., B. P.), containing gentian, bitter orange peel, and cardamom, 2-16 c.c. (|-4 fl. drs.). Infusum Gentians? Compositum (B. P.), containing gentian, bitter orange peel, and fresh lemon peel, \-\ fl. oz. Quassia (U. S. P.), Quassiae Lignum (B. P.), the wood of PicraBua excelsa, contains several neutral bitter substances, resembling each other closely chemically and known as quassiins. EXTRACTUM QUASSIA (U. S. P.), 0.05-0.2 G. (1-3 grs.). Fluidextractum Quassice (U. S. P.), 0.5-2 c.c. (5-30 mins.). TINCTURA QUASSIA (U. S. P., B. P.), 1-4 c.c. (15-60 mins.). Liquor Quassise. Concentratus (B. P.), |-1 fl. dr. INFUSUM QUASSIA (B. P.), \-\ fl. oz. Calumba (U. S. P.), Calumbse Eadix (B. P.), columbo, the root of Jateor- rhiza palmata, or Columba, contains columbin, a neutral body, columbic acid, and the alkaloid berberine. Fluidextractum Calumbce (U. S. P.), 1-2 c.c. (15-30 mins.). TINCTURA CALUMBCE (U. S. P., B. P.), 4-15 c.c. (1-4 fl. drs.). Infusum Calumbce (B. P.), ^-1 fl. oz. Liquor Calumbce, Concentratus (B. P.), ^-1 fl. dr. Chirata (U. S. P., B. P.), Chiretta, the plant Swertia chirata, contains a glucoside, chiratin, and ophelic acid. Fluidextractum Chiratw (U. S. P.), 0.3-1 c.c. (5-15 mins.). Tinctura Chiratce (B. P.), 4-8 c.c. (1-2 fl. drs.). Liquor Chiratce Concentratus (B. P.), -1 fl. dr. Infusum Chiratce (B. P.), \-\ fl. oz. Taraxacum (U. S. P.), Taraxaci Radix (B. P.), the root of the dandelion, SIMPLE BITTERS. 59 Taraxacum officinale, contains two neutral bitter substances taraxacin and taraxacein. Extractum Taraxaci (U. S. P., B. P.), 0.3-1 G. (5-15 grs.). Fluidextractum Taraxaci (U. S. P.), Extractum Taraxaci Liquidum (B. P.), 4-12 c.c. (1-3 fl. drs.). Succus Taraxaci (B. P.), 1-2 fl. drs. Berberis (U. S. P.), barberry, the rhizome and roots of various species of Berberis, contains berberine and tannin, 2 G. (30 grs.). Fluidextractum Berberidis (U. S. P.), 2 c.c. (30 mins.). Pareira (U. S. P.), Pareirae Radix (B. P.), the root of Chondrodehdron tomentosum, contains an alkaloid, buxine. Fluidextractum Pareifce (U. S. P.), Extractum Pareivce Liquidum (B. P.), 2-8 c.c. Q-2 fl. drs.). Serpentaria (U. S. P.), Serpentariae Rhizoma (B. P.), snake-root, the rhi- zome and roots of Aristolochia serpentaria and of Aristolochia recticulata, contains a volatile oil, an unknown bitter principle, and perhaps an alkaloid, aristolochine. Fluidextractum Serpentarice (U. S. P.), 1-2 c.c. Tinctura Serpentaria (U. S. P., B. P.), 2-8 c.c. (-1 fl. dr.). Liquor /Serpentarice Concentratus (B. P.), 5 2 fl. drs. Infusum /Serpentarice (B. P.), ^-1 fl. oz. Hunmlus (U. S. P.), Lu.pu.lus (B. P.), hops, the strobiles of Humulus lupu- lus, and Lupulin, a glandular powder separated from hops, contain a volatile oil, a bitter neutral substance, lupulin, lupulinic acid, and resins. Fluidextractum Lupulini (U. S. P.), 2-8 c.c. (-2 fl. drs.). Oleoresina Lupulini (U. S. P.), 0.1-0.3 G. (2-5 grs.). Lupulinum (B. P.), 2-5 grs. Infusum Lupuli (B. P.), 1-2 fl. oz. Tinctura Lupuli (B. P.), i-1 fl. dr. Cuspariae Cortex (B. P.), Angostura bark, the dried bark of Cusparia feb- rifuga, contains four or more alkaloids, cusparine, cusparidine, galipine, and galipidine, along with a volatile oil and a neutral bitter stuff. Infusum Cusparise (B. P.), 1-2 fl. oz. Liquor Cusparise. Concentratus (B. P.), -1 fl. dr. Nectandrae Cortex, Bebeeru bark, is not pharmacopoeial, but is occasion- ally used in therapeutics. It contains an alkaloid which is now known to be buxine, but which has been called beberine, biberine, or bebeerine hitherto. Buxine or beberine sulphate is prepared from it. Condurango, the bark of Goiiolobus condurango, contains two glucosides of similar properties, and has been used a good deal of late years as a stom- achic bitter. It was formerly credited with a specific action on epithelioma. Cetraric acid, or cetrarin, is obtained from Iceland moss (see page 47), and has been recommended as a bitter in doses of about 0.1 G. (2 grs.), in tablets. Coto bark, whose origin is still doubtful, contains cotoin (C^HisOe), aiu l has been used to form a fluid extract. Dose, 0.3-1.5 c.c. (5-20 mins.). Cotoin has been prescribed in the dose of 0.03-0.2 G. (-3 grs.). Orexine Hydrochlorate, C6H4NoC2H3C6H5HCl, is a colorless, crystalline body, soluble in about 15 parts of water, with a bitter, somewhat pungent taste. It is prescribed in powder or tablets. Dose, 0.3 G. (5 grs.). Bael fruit, or Bengal quince, was formerly contained in the B. P., but has been omitted in the last edition. Very little is known regarding its action or principles, but it may perhaps have some effect as a bitter. Many other bitter stomachics might be enumerated, some of which have been used largely in former times, but as they are all identical in their effects, it seems unnecessary to do so. Instead of the simple bitters, cinchona and mix vomica preparations are often used in small quantities. Many of the preparations which 60 ORGANIC SUBSTANCES ACTING LOCALLY. will be enumerated under the volatile oil series owe much of their effect to the bitter which accompanies the volatile oil, and in numerous other pharmacopreial preparations bitters are present, although their eifect is hidden by the action of the drug in other directions. Therapeutic Uses. The bitters are used chiefly to increase the appe- tite and the digestion. In convalescents, in persons of sedentary habits, and occasionally in chronic dyspeptic conditions they are of value, while in cases of more acute gastric irritability they may do harm rather than good. Gentian, Quassia, Calumba and Chirata are the only simple bitters that are largely used, and the first is much the most important. They are generally prescribed as tinctures, fluid ex- tracts or other fluid preparations. The last three may be prescribed with iron preparations, as they contain little or no tannic acid and thus cause no precipitate. Pills are sometimes prescribed with extract of gentian or quassia, but it seems open to question whether these in- gredients have really any eifect when given in this form. Compound tincture of gentian is sometimes used to give flavor rather than for any effect on the digestion. Quassia infusion (ten per cent.) is injected as an enema in the round worms of children. Several of the drugs mentioned, such as taraxacum and gentian, have been supposed to have a specific action on the liver, but there are no sufficient grounds for this belief. The supposed virtues of pareira as a diuretic and of berberine, buxine, and other alkaloids as substitutes for quinine in ma- laria have also proved to have no foundation, and the popular reputation of hops as a narcotic probably arises from its association with alcohol in beer. Cotoin and Goto bark are said to have some special effect in lessening diar- rhoea, in addition to their action as bitters. BIBLIOGRAPHY. Bokai, Reusz, Vas, Huber and Gara. Ungar. Arch, fur Medicin, ii., pp. 295-325. Gottlieb. Arch. f. exp. Path., xxxiii., p. 261. Brandl Zts. f. BioL, xxix., p. 277. Scanzoni. Ibid., xxxiii., p. 462. Jodlbauer. Arch, internal, d. Pharmacodyn., x., p. 201. Pawlow and Schumowa-Simanowskaja. Arch. f. [Anat. u.] Phys., 1895, p. 53. Binz. Virchow's Arch., xlvi., p. 129. Jukna. Arb. des pharmak. Instit. Dorpat, iv., p. 81. (Coridurango.) Pohl. Arch. f. exp. Path. u. Pharm., xxix., p. 282. (Aristolochine.) Farkas. Pfliiger's Archiv, xcii., p. 61. (Lupulinic acid.) K. v. Bunye. 'Arb. des pharmak. Institut. Dorpat, xi.-xii., p. 135. (Berberine.) Mosse u. Tautz. Ztschr. f. klin. Med., xliii., p. 257. Ramm. Historische Studien a. d. pharmak. Instit. Dorpat, ii., p. 1 . Borissow. Arch. f. exp. Path. u. Pharm. Ii., p. 363. Karb. Deut. Arch. f. klin. Med., Ixxvi., p. 30. (Goto.) Reichmann. Ztschr. f. klin. Med., xiv., p. 177. Kobert. International Congress Berlin, 1890, iv., p. 58. (Cetrarin.) Penzoldt. Therap. Monatsh., 1890, p. 59. (Orexine. ) Kronfeld. Wiener klin.. Woch. f 1891, p. 45. (Orexine. ) VOLATILE OIL SERIES. 61 V. VOLATILE OIL SERIES. The group of volatile, ethereal, or essential oils contains a large number of preparations in the pharmacopoeias of all countries. These oils are obtained from plants by distillation, or more rarely by pres- sure, and must be distinguished by the student from the fatty or fixed oils, which are non-volatile. The volatile or ethereal oils are found chiefly in the fruits and flowering parts of plants, and are very widely diffused through the vegetable kingdom, though some orders, such as the Labiatse, Umbelliferse, Aurantiacese, Cruciferse, and Conifers are preeminent in their production. They are all strongly odorous, and are therefore used in perfumery, and to conceal nauseous odors and tastes in medicine. Their composition is extremely variable. The commonest constituents are Terpenes, and some oils contain these only, while in a few oils no terpene has been found (Attar of Roses). Terpenes are hydrocarbons of the aromatic series, and possess the general formula (C 5 H 8 ) n . The great majority of them, or the terpenes proper (C 10 H 16 ), are combinations of a dihydrobenzol with propyl and methyl (C 6 H 4 (H 2 )C 3 H 7 CH 3 ). Some twelve terpenes of this formula are known, varying in their chemical structure and in their stereometrical form. Another group of these hydrocarbons is formed by the Sesquiterpenes (C 15 H 2 J, while a few Diterpenes (C 20 H 32 ) are known. Some volatile oils consist of these hydrocarbons only, but many of them contain in addition some oxidized aromatic substances, such as phenols, ketones, aldehydes, acids and their compounds ; as instances of these may be cited camphor, thujon (from oil of absinth), sabinol (oil of savine), safrol, thymol, eucalyptol, myristicol, and vanillin. Many of these oxidized products crystallize out when the volatile oil is cooled sufficiently, and especially on long standing, and the resulting solid is known as a Stearoptene, while the fluid remaining is sometimes called Elceoptene. The oils containing oxygen are not so volatile as the pure hydrocarbons, but the odor is often due chiefly to the oxidized substances. A very few oils contain nitrogenous bodies, generally in the form of cyanides, while, on the other hand, the majority of the volatile oils of the Cruciferse contain sulphur bodies, which lend them a pungent, disagreeable odor, quite different from that of the other oils. The volatile oils are generally clear, colorless fluids, although some of them are green from the presence of small quantities of vegetable coloring matter, while others are blue in color from the presence of a terpene derivative (azulene). After long keeping they often acquire a yellowish color and an acid reaction, from the formation of resins. They are generally light, sparkling fluids, but the oils of copaiva and cubebs are more viscid. They are insoluble in water except in very small amount, which, however, is enough to lend their characteristic odor to the solution ; in strong alcohol, ether, benzol, chloroform, and fixed oils, they are freely soluble. Many of the plants from which the volatile oils are obtained possess other active constituents, such as bitters, and as many of the prepara- tions used in therapeutics are formed, not from the distilled oils, but from the crude parts of plants, it must be noted that the oil is not the only active principle in them. A series containing members which differ so widely chemically, and which in fact have only their volatility and their aromatic nucleus in common, could not be expected to have 62 ORGANIC SUBSTANCES ACTING LOCALLY. a uniform action in the animal organism. It is found, however, that they resemble each other in their therapeutic properties, because they are used almost solely for their local action, and that in only small quantities. Some of the volatile oil preparations which are employed for their general effects, will be discussed later. (See Camphor.) Action Externally. The volatile oils all possess antiseptic properties, which are doubtless due in part to their volatility enabling them to penetrate readily into protoplasm and to lessen its vitality by acting as foreign bodies. In addition, they are nearly related to the benzol series, the members of which are all antiseptics and protoplasm poisons. They differ a good deal in their germicidal power, and are much more poisonous to the moulds than to the bacteria. The most active oils are those containing a large amount of terpene, such as the oil of tur- pentine. Their volatility may also explain their irritant action in part, for most other volatile substances are more or less irritant, but here again their relation to the phenols and benzol cannot be ignored. Applied to the skin, they cause redness, itching and warmth, owing to a local dilation of the vessels, which may be due to the penetration of the oil to the cutaneous arterioles or veins, or to a reflex from the irritated terminations of the sensory nerves acting on the vasomotor centres. When painted on the mucous membranes, such as those of the eye or nose, or on wounds, the volatile oils cause similar irritation, which is betrayed by redness and congestion, pain and smarting. Action on the Alimentary Canal. Strong solutions of the oils act as irritants in the mouth. They have generally a hot, burning taste, and if kept in the mouth, cause redness and irritation of the mucous membranes, although some of them induce a sense of coolness at first. At the same time the organs of smell are affected by these oils, which are almost all possessed of characteristic odors. The irritation of the mouth leads to a reflex secretion of saliva, which is often very profuse. The antiseptic action of the oils is exercised in the mouth as elsewhere, and may have a beneficial effect in some conditions. On passing into the stomach, the oils cause the same sensation of warmth in that organ, and this is accompanied by a sense of well- being and comfort, the appetite is often increased, and any feeling of distention after meals is relieved. This is often attended by the eruc- tation of quantities of gas. Substances which produce these effects in the stomach are known as carminatives, and many explanations of their action have been offered. The oils undoubtedly act as antiseptics here as elsewhere, and may hinder the development of yeasts and other organisms and thus be of benefit, but this would not give the imme- diate feeling of relief which is often experienced after a small quantity of these remedies. The process of digestion seems to be rather re- tarded than accelerated by the presence of the oils, as far as can be .adged by test-tube experiments and by some measurements made by Suchheim on the digestion of animals with gastric fistulse. The secre- tion of the gastric glands has been said to be increased by the direct VOLATILE OIL SERIES. 63 action of the volatile oils, but this has been disputed. But it must not be forgotten that the most powerful stimulant to gastric secretion is the smell and taste of food, and that substances of agreeable taste and odor cause a marked increase in the gastric juice by reflexes from the mouth and nose. An argument for the direct action of the volatile oils on the secretory glands has been drawn from the observation that, applied to the frog's skin, they induce a profuse local secretion, but this is scarcely sufficient basis for an explanation. The eructation of gas certainly suggests that the volatile oils accelerate the movements of the stomach, and this has been repeatedly confirmed by the direct observa- tion of the stomach walls. Brandl has also shown recently that absorp- tion occurs much more rapidly from the stomach in the presence of slight irritants, such as the volatile oils. Finally it must be added that many of the beneficial effects are purely subjective ; the patient has a feeling of warmth and comfort in the region of the stomach, arising from the slight irritation and consequent hyperaBmia of the mucous membrane, but this does not necessarily indicate any marked altera- tion in the processes of digestion or in the movements of the stomach. Similar effects are believed to be produced in the intestine, for the administration of these oils is often followed by an improvement in its condition, manifested by lessened flatulence and distention, and relief is given by their use in some forms of colic. The antiseptic action may play a part in these effects. Scanzoni and Farnsteiner have recently shown that the intestine, like the stomach, absorbs more rapidly in the presence of small quantities of the oils. The pancreatic secretion was supposed to be increased by their irritant action in the stomach, through a reflex travelling both centripetally and centrifugally along the vagus fibres (Gottlieb), but Schirokikh asserts that this is true only when large quantities produce very marked gastric irritation. Whether the peristaltic movements of the bowel are increased by the volatile oils is quite unknown. It is believed, however, that their administration lessens the pain and griping produced by some of the more powerful purgatives, and several pharmacopoeial preparations are formed on this theory, which is supported by many years of clinical experience. A considerable increase in the leucocytes of the blood follows their ingestion by the mouth, but this is observed in congestion of the stomach and intestine from other causes and is not induced by the sub- cutaneous or intravenous injection of the volatile oils, so that it cannot be regarded as a specific effect. Winternitz found that irritation of the pleura causes less purulent exudate in animals treated with some volatile oils than in controls which were not treated in any way, and concludes that the presence of the oils in the blood lessens the exudate and also promotes its absorption ; he is inclined to regard this anti- phlogistic action as a result of the leucocy tosis and of a supposed attrac- tion exercised on the leucocytes by the oils, which prevents their wander- ing into the tissues. Excretion. Like other bodies of the aromatic series, they tend to undergo a partial oxidation in the body ; thus the terpenes (C 10 H 16 ) 64 ORGANIC SUBSTANCES ACTING LOCALLY. become terpenols (C^H^OH), and several derivatives of the terpenes have been shown to undergo a similar change of a hydrogen atom to hydroxyl, while others which contain the -OH group originally, remain unaltered. The odor of the original oil or of these derivatives may often be detected in the breath, showing that a small part is excreted by the lungs, and possibly traces may be eliminated by the skin. Some also escapes by the kidney uncombined and imparts an odor to the urine either of the original oil or of some oxygen derivative ; for instance, oil of eucalyptus or of turpentine gives the urine a violet odor. But much of the hydroxyl product is combined with glycuronic acid and escapes in the urine in this form, while some may combine to form conjugate sulphates. The glycuronic acid reduces Fehling's solution, especially when the urine is previously boiled with acid, so that the volatile oils were formerly credited with inducing glycosuria. Some of the constituents of the oils are oxidized to acids and excreted in the urine as salts. In the course of excretion, some of the oils cause irritation of the lungs and kidneys, so that some of them are employed to increase the bronchial secretion, while others have a distinct diuretic action. This irritant action is- of course not confined to the tissue, but extends to microbial guests, so that the volatile oils have been given internally with the intention of destroying or retarding the growth of bacteria in the lungs, and some of them are used almost exclusively for their anti- septic action in the urine. Poisoning. The various oils differ a good deal in their activity, while resembling each other closely in the general characters of their effects. All of them may produce marked irritation of the stomach and bowel when given in large quantities, but the oils of tansy, sage, and English pennyroyal are distinguished especially by the violent in- flammation they cause, and by the frequency with which fatal poison- ing occurs from their use. The terpenes appear to be but slightly poisonous, and their effects are probably limited to local irritation ; the oxidized aromatic substances have been shown to be the poisonous con- stituents in all the oils hitherto examined. The symptoms are those of acute gastric, intestinal, and often renal irritation vomiting, purg- ing, acute pain in the abdomen, blood in the stools and in the vomited matter, collapse, weakness of the pulse and respiration, anuria, or albumin and blood in the urine, and convulsive attacks ending in coma and death. Great hypersemia of the abdominal organs, often blood in the peritoneal cavity, and sometimes acute inflammation of the kidney are the chief post-mortem appearances. The hypersemia and conges- tion of the organs of the abdomen may cause abortion in pregnancy, or increase the menses, and in the majority of cases of poisoning, these oils have been taken with the object of inducing abortion. In many instances, however, the drug has proved fatal without this end being achieved. VOLATILE OIL SERIES. 65 General Action. The small quantities of volatile oils administered in or- dinary medicinal use pass through the tissues without modifying them per- ceptibly, their only effects arising in the organs by which they are absorbed and excreted. In large quantities, however, some of them (the oils of worm- wood, nutmeg, sage, savine among others) produce symptoms which indi- cate an affection of the central nervous system quite apart from their local action. The latter also produces nervous effects reflexly, and it has been found exceedingly difficult to distinguish these indirect results from those caused by the direct action on the central nervous system. A good deal of divergence is to be found in the statements of different writers from this cause, and also from the fact that comparatively few researches have been carried out with pure principles. Many of the oils vary in their constituents accord- ing to the climate, the season of the year, and other conditions under which the plant was grown, and some of the confusion may arise from differences in the oils used by investigators. Almost all the oils hitherto examined cause depression and final paralysis in the frog. The action seems to be mainly on the brain, larger quantities being required to paralyze the spinal cord than to prevent all spontaneous movements. This stage of depression is preceded by one of excitement after oil of wormwood and some others. Some of the oils paralyze the terminations of the motor nerves in voluntary muscle like curara and camphor. In mammals the general action of the constituents of the volatile oils seems to involve a preliminary stimulation and subsequent depression of the nerve cells. The relative importance of these two stages differs in different oils, some, e. y the same segment; of tnTspin'al "cord or brain. Thus in painful diseases of the stomach, ten- derness is often complained of in the skin of the epigastrium, while in oesophageal stricture, pain is often referred to a point near the angle of the scapula and to another in the neighborhood of the apex-beat. The superficial points are, of course, only connected with the diseased organ by means of nerve-fibres, but Head's observations show that a nervous impulse from these organs does not pass in an indeterminate manner through the central nervous system, but has a distinct tendency to affect the superficial areas which are supplied with sensory nerves from the same segment of the cord. It would, therefore, seem a plaus- ible theory that an affection of these superficial areas may affect the corresponding internal organ more than the rest of the body, and this is exactly what is required to explain the benefits derived from the use of counter-irritants. It is especially noticeable that several of the points which Head observed to be affected by internal disease are precisely those points at which experience has shown irritation to be most beneficial. (Fig. 1.) Thus the application of a blister over the epigastrium has long been recognized as a means of relieving gas- tric disorders. Similarly the old treatment of iritis by means of a blister on the temple may be justified by the fact that Head found areas of tenderness on the temple accompanying this disease. The exact nature of the effects of counter-irritation on the internal organs has not been ascertained, but it would seem most probable that an alteration in the calibre of the vessels and in thej^sory nerves or their terminations is induced. These alterations may, however, pro- duce or be accompanied by a distinct alteration in the activity of the organs ; for example, there seems good reason to believe that in many cases irritants applied to the abdomen produce evacuation of the bowels. Besides these physiological effects of counter-irritation, it must not be forgotten that a great impression is produced on the patient, and that some of the benefit may be due to hypnotic suggestion. Therapeutic Uses. Local irritants are" applied occasionally to pro- duce an alteration in the nutrition and blood supply of the skin itself and of the subcutaneous tissues. Thus in some chronic inflammatory SKIN IRRITANTS AND COUNTER-IRRITATION. 83 conditions, with effusions into, or indurations of the subcutaneous tis- sues, the improvement of the circulation produced by slight irritation FIG. 1. The right side is divided into segments which correspond to some of the skin areas in which Head found tenderness in internal diseases. 1. Area of tenderness in disease of the lungs. 2. In diseases of the stomach. 3. In ovarian disease. 4. In disease of the Fallopian tubes and other appendages. On the left side are represented the points of application of counter-irritants in disease of the lungs (A), of the stomach (B), of the ovary (C), and of the uterine appendages (Z>). may be of benefit. An example of this is the treatment of ulcers of old standing with irritants. Another case in which a slight inflamma- tory attack causes very obvious improvement, is in corneal opacity, which may be removed entirely in some cases by the acute inflam- matory reaction produced by such irritants as abrin. Probably a similar effect is produced on subcutaneous effusions, as in bruises. Some interesting experiments on this subject have recently been per- formed by Wechsberg, who induced suppuration in both hind legs of rabbits by the injection of irritants and then treated the one leg by the application of various irritants to the skin, while the other was left untreated as a control. He invariably found the abscess of the leg subjected to treatment less extensive and showing a greater tendency to heal than the other, and accounts for this by the oedema induced by the skin irritant diluting the original irritant and promoting its absorption. The increased blood supply leads to a larger number of leucocytes and more alexines around the inflammation than would otherwise be present. He found that the absorption of pigments from 84 ORGANIC SUBSTANCES ACTING LOCALLY. the rabbit's ear was much accelerated by the application of irritants to the skin over the part, and cites this as evidence that toxines are removed more rapidly under similar treatment. For these purposes only the milder irritants are required ; in fact, vesication may do more harm than good. Mild irritation alters the sensitiveness of the sen- sory organs of the skin, and heat is often applied to alleviate pain and discomfort in the skin itself. In other instances pain is increased by heat, and, in fact, it is sometimes applied in the treatment of local anaesthesia, with the object of rendering the surface more sensitive. In many forms of skin disease, mild irritants are found to be of bene- fit ; this is sometimes attributed to their antiseptic action, but the slight irritation is undoubtedly of some importance. Counter-irritants are used in a large number of diseases, often with- out any definite idea of what precise effects they will elicit, but merely because they have been found to give relief in similar conditions. As a general rule they are placed over the affected organ, and this corre- sponds fairly in most cases of disease of the trunk with Head's area of skin tenderness. In the head, however, the segmental arrangement has been rendered very irregular by the compression in development, and counter-irritants are often found to be most effective when placed at some distance from the seat of pain, e. #., behind the ear in some forms of facial neuralgia. They are used in acute inflammation of the lungs and pleura, in gastric disorders accompanied by much pain, in colic and in neuralgia and neuritis. Their action is very uncertain, but their application is often followed by great relief, more especially of pain. They are also used occasionally in shock or collapse, not for their effect on any individual organ, but to elicit the reflex alterations in the circulation which have already been described. A blister is often recommended in internal haemorrhage, and may very possibly lessen the bleeding by altering the distribution of the blood in the organs, although it is difficult to estimate how far the improvement is due to the remedy and how far it is spontaneous. In order to produce any marked effect on internal organs, the more powerful irritants must be used, such as mustard or cantharides. It is not necessary, however, to produce actual vesication in the great majority of cases. Formerly blisters were opened and fresh irritants applied on the raw surface in order to prolong the effects, but this treatment was extremely painful, besides being liable to set up suppuration and ulceration, and it is very questionable whether any equivalent benefit followed. Counter-irritation must be applied only with the greatest caution in weak, badly nourished, or very old persons, as it may cause sloughing. In diabetes, the tendency to gangrene contraindicates blistering, and in very young children only mild irritants are used. BIBLIOGRAPHY. Naumann. Vierteljahrsch. f. prakt. Heilkunde, Ixxvii., p. 1, and xciii., p. 133. Ziilzer. Deutsche Klinik., 1865, p. 127. Rohrig. Ibid., 1873, p. 209. fliiger' Paalzow. Ibid., iv., p. 492. Rohrig and Zuntz. Pfliiger's Arch. ? iy., p. 57. SKIN IRRITANTS AND COUNTER-IRRITATION. 85 Wertkeimer. Arch, de Phys., 1894, pp. 308 and 724. Hddenhain. Pfliiger's Arch., iii., p. 504; v., p. 77. Riegel. Ibid., iv., p. 350. Mantegazza. Schmidt's Jahrb., cxxxiii., p. 153. Jacobson. Virchow's Arch., Ixvii., p. 166. Head. Brain, xvi., p. 1 ; xvii., p. 339. Schuller. Berl. klin. Woch., 1874, p. 294. Winternitz. Arch. f. exp. Path, und Pharm., xxxv., p. 77 ; xxxvi., p. 212. Wesseley. Centralbl. f. Chirur., xxx., No. 36. Hay. Saline Cathartics, pp. 128-144. Buthner, Fuchs, Megele. Arch. f. Hygiene, xl., p. 347. Wechsberg. Ztschr. f. klin. Med., xxxvii., p. 360. An enormous number of drugs produce irritation of the skin, and it would be idle to attempt to enumerate them here. In many in- stances, however, the irritant action is insignificant in comparison with the other effects produced, and these will, therefore, be discussed else- where; among these are found some of the alkaloids, the acids and alkalies, and many other inorganic preparations. Irritation of the skin may also be produced by heat and cold, and in fact burning in various forms was formerly used as a means of counter-irritation. Heat is still employed to cause irritation of the skin and subcutaneous tissues, and to promote their circulation. Thus, poultices and hot water com- presses are beneficial in many local inflammations, though the same effects may generally be obtained by the use of the milder irritants. The effect of cold on the skin is more frequently demonstrated by bathing, and will be touched on in relation to the antipyrine series. Apart from those drugs in which the irritation of the skin is merely an incident in a wider general action, there are a number of prepara- tions which are used almost exclusively for this purpose. They may be divided into three classes : the volatile irritants, such as turpentine oil; the mustard series, some of which are also volatile; and those which are either non-volatile or only boil at high temperatures, such as cantharidin. I. The Turpentine Oil Group. Under the volatile irritants may be included a large number of the ethereal oils and many members of the methane and of the aromatic series; but among the ethereal oils those which possess a low boiling point, that is, those which contain a large proportion of terpene, with comparatively little oxygen, are found to possess a more penetrating action than the others. At the same time, the taste and odor of these oils is often less pleasant than that of the others, so that they are less used as flavors and carminatives. The oils derived from the Coni- ferse have, for this reason, been more largely used than the others for their effect on the skin, although several other volatile preparations are recognized by the pharmacopoeia for this purpose. The action of these oils is similar in other respects to that of the general group (see p. 61), so that it need not be discussed here. PKEPA RATIONS. Terebinthina, turpentine (U. S. P.), Thus Americanum, Frankincense (B. P.), a concrete oleoresin obtained from Pinus palustris and other species of Pinus. 86 ORGANIC SUBSTANCES ACTING LOCALLY. Terebinthina Canadensis (U. S. P., B. P.), Canada balsam, a liquid oleo- resin obtained from Abies balsamea. Fix Burgundica, Burgundy Pitch (B. P.), an oleoresin derived from Abies excelsa, Norway spruce fir, contains less volatile oil than turpentine. OLEUM TEREBINTHINA (U. S. P., B. P.), oil of turpentine, a volatile oil distilled from turpentine. Oleum Terebinthince Rectification (U. S. P.), is formed from ordinary oil of turpentine by redistillation with lime water, in order to remove any acids and resin which may be contained in it. It consists of a mixture of terpenes (C 10 H 16 ). Dose, 1 c.c. (15 mins.); as an anthelmintic, 8-15 c.c. (2-4 fl. drs.). Emulsum Old Terebinthince (U. S. P.), 4 c.c. (1 fl. dr.). Linimentum Terebinthince (U. S. P., B. P.). Linimentum Terebinthince Aceticum (B. P.), is formed by mixing turpentine, glacial acetic acid and camphor liniment. Emplastrum Picis (B. P.), pitch plaster. Oleum Pini (B. P.), the oil distilled from the fresh leaves of Pinus pumilis. Terebenum (U. S. P., B. P.), a liquid formed from oil of turpentine by the action of sulphuric acid. It consists of a number of terpenes, one of which is the pure substance known as terebene. Its odor is more pleasant than that of turpentine oil, which it closely resembles in most other points. Terpini Hydras (U. S. P.), terpin hydrate, is a crystalline substance (C }0 H 16 (OH) 2 + H 2 O) derived from oil of turpentine by the action of nitric acid in the presence of alcohol and water. It possesses almost no odor, is insoluble in water, and melts at about 116 C. Sabina (U. S. P.), the tops of Juniperus sabina, savine, contains as its ac- tive principle Ol. Sabinse, a volatile oil which resembles that of turpentine in many respects, but is not identical with it. Oleum Juniper! (U. S. P., B. P.), oil of Juniper, is derived from the jum- per berries and consists mainly of terpenes. Dose, 0.03-0.2 c.c. (-3 mins.). Spiritus Juniperi (U. S. P., B. P.), 1-4 c.c. (15-60 mins.). Spiritus Juniperi Compositus (U. S. P.), 4-8 c.c. (1-2 fl. drs.). In addition to these preparations the following may be mentioned here as possessing similar action and uses. Linimentum Chloroformi (U. S. P., B. P.). Linimentum Camphorse (U. S. P., B. P.). Linimentum Camphorse. Ammoniatum (B. P.). Linimentum Saponis (U. S. P., B. P.), very slightly irritant. Emplastrum Arnicse (U. S. P.). Ceratum Camphorss (U. S. P.). Therapeutic Uses. Turpentine oil is used externally as a rubefacient, and differs from mustard and cantharidin in its greater penetrating power. It is not so irritant, however; it blisters only after long appli- cation, and the vesication produced is very painful and heals slowly, from the vapor penetrating into the deeper tissues. It is, therefore, employed to produce rubefaction only, and ought to be removed when this is attained. For this purpose any of the liniments of the group may be employed, or a more intense action may be got from the " tur- pentine stupe," which is made by dipping flannel in hot water, wringing it dry, and then dropping warm turpentine oil on it. 1 Turpentine preparations are used especially in rheumatic affections of the joints or muscles, and in sciatica. The oleoresins may be formed into ointments, 1 Alcohol has recently been applied in a similar way in phlegmon and other forms of inflammation. Gauze is soaked in alcohol (60-96 per cent. ), wrung out, wound round the affected part and covered with cotton and oil-cloth. SKIN IRRITANTS AND COUNTER-IRRITATION. 87 or plasters, and used as feeble stimulants in skin diseases. Turpen- tine oil is a fairly strong antiseptic, and is less irritant than many of the more powerful ones. It is often inhaled in lung diseases such as tuberculosis or gangrene, and has the effect of lessening the odor in the latter; the oil may be simply allowed to evaporate, but is much more efficient when sprayed into the air. Many of the resorts for phthisical patients are stated to be rendered especially suitable for the treatment of this disease by the neighborhood of coniferous forests, which are supposed to dissipate the oils into the atmosphere ; but this is probably only an insignificant factor in the treatment. Turpentine oil is occasionally added to baths in order to cause a slight general stimulation of the skin, which may be of benefit in some skin diseases and also in general debility under certain conditions ; and pine-needle baths have some reputation in Germany for the same reason, the water being supposed to extract the oil. Internally, turpentine oil is occasionally employed as a vermifuge, but is inferior to other preparations used for this purpose. A few drops are often added to purgative enemata to increase their efficiency. It has been given by the mouth in order to lessen flatulence and to disinfect the intestine in various diseases, among others, typhoid fever, although its value here is disputed. Preparations of turpentine oil and juniper are reliable and fairly powerful diuretics, but must not be prescribed in irritation of the kidney. The turpentine preparations have a cer- tain reputation as expectorants, and terebene has been especially ad- vised for this purpose ; they are also given internally as pulmonary disinfectants. In some forms of neuralgia their internal administration has been found beneficial, and oil of turpentine has been used in internal hemorrhage, but with doubtful results. Old oil of turpentine was formerly advocated in phosphorus poisoning, but this treatment has proved to be valueless. Along with these may be mentioned a series of resins which have some slight irritating effect on the skin, and have been used in the treatment of skin dis- eases. Resina (U. S. P., B. P.), resin, colophony, is the residue left after distilling off the volatile oil from turpentine. Ceratum Reduce (U. S. P. ). Ceratum Resince Compositum (U. S. P.). Emplastrum Resince HJ. S. P., B. P.), adhesive plaster. Unguentum Resince (B. P.). Galbanum (B. P.), a gumresin obtained from Ferula galbaniflua and prob- ably from other species. It contains some volatile oil, gums and resin. Dose, 5-15 grs. Pilula Galbani Composita (see Asafcetida). Ammoniacum (B. P.), a gumresin obtained from Dorema Ammoniacum, and containing a small quantity of a volatile oil with an unpleasant odor. Emplastrum Ammoniaci cum Hydrargyri (B. P.). Mistura Ammoniaci (B. P.), -1 fl. oz. Guaiaci Lignum (B. P.), the heart- wood of Guaiacum officinale. Guaiacum (U. S. P.), Guaiaci Resina (B. P.), the resin obtained from Guaia- cum officinale, contains several resinous acids, some volatile oils and gums. It is colored deep blue by oxidizing agents. 88 ORGANIC SUBSTANCES ACTING LOCALLY. Tinctura Guaiaci (U. S. P.), 4 c.c. (1 fl. dr.). Tinctura Guaiaci Ammoniata (U. S. P., B. P.), 2-4 c.c. (-1 fl. dr.). Mistura Guaiaci (B. P.), -1 fl. oz. Trochiscus Guaiaci Resinse (B. P.), each containing 3 grs. Elemi resin (not official) is obtained from a number of trees of the order Burseracea?, and contains volatile oil and resins. Unguentum Elemi (not official). Myrrha (U. S. P., B. P.), a gumresin obtained from Commiphora Myrrha (U. S. P.), from Balsamodendron Myrrha (B. P.), containing a small quantity of volatile oil. Tinctura Myrrhse (U. S. P., B. P.), 2-4 c.c. (\-l fl. dr.). Pilultz Aloes et Myrrhx (U. S. P., B. P.). Tinctura Aloes et Myrrhse (U. S. P.). Mistura Ferri Composita (U. S. P.). Many other resins have been used in therapeutics, but have been aban- boned, a fate by which these survivors seem to be threatened. They are occasionally used externally as mild irritant applications in skin affections. Galbanum, Ammoniacum, Guaiacum and Myrrh have been used internally for many different purposes, as expectorants, diaphoretics, diuretics, aperi- ents, and have enjoyed a reputation in the treatment of amenorrhcea. They may be used to suspend insoluble bodies, as the gum contained causes them to form emulsions when water is added. II. Mustard. Mustard occurs in two forms in the pharmacopoeias, Black Mustard, Sinapis nigra, and White Mustard, Sinapis alba. Black Mustard con- tains a glucoside, Potassium Myronate or Sinigrin, and a ferment, Mi/rosin, which decomposes it in the presence of water into dextrose, potassium bisulphate and allyl-isosulphocyanate or volatile oil of mustard. Sinigrin. Volatile oil. C 10 H 18 KNS 2 10 = CSNC 3 H 5 + C 6 H 12 O 6 + KHSO 4 Volatile oil of mustard is formed in various other Cruciferae when they are mixed with water. Thus horseradish root (Armoracia, B. P.) contains it, while the allied species Cochlearia officinalis apparently contains the corre- sponding isobutyl compound. White mustard contains another glucoside, Sincdbin, which is also decomposed by the Myrosin in the presence of water. The products are entirely different, however, dextrose, sulphate of sinapine (an alka- loid), and an oil of mustard containing an aromatic nucleus being formed. Sinalbin. Oil of Mustard. Sinapine Sulphate. 2 S 2 16 = C 6 H 4 (OH)CH 2 NCS + C 16 H 23 NO 5 H 2 SO 4 + C 6 H 12 O 6 The oil of white mustard differs from that of the black in being less irritant, and in being destroyed by heat. Action. Either of these oils is intensely irritant when applied to the skin, and if left long enough produces blistering, which is more painful than that caused by cantharides, and is said to heal less readily. This is probably due to the oils penetrating more deeply into the tissues, and thus setting up more extensive inflammation. Mustard is accord- SKIN IRRITANTS AND COUNTER-IRRITATION. 89 ingly used only to induce rubefaction, and ought to be removed before actual vesication occurs. When the crude drug is moistened and ap- plied to the skin, the oil is formed only slowly, so that the longer it remains applied, the more intense is the action. The glucosides in themselves have little or no action, and the products of their decom- position are harmless, with the exception of the oils. PREPARATIONS. Sinapis Alba (IT. S. P.), Sinapis Albae Semina (B. P.), the dried ripe seeds of Brassica alba. Sinapis Nigra (U. S. P.), Sinapis Nigrse Semina (B. P.), the dried ripe seeds of Brassica nigra. Sinapis (B. P.), a mixture of the powdered seeds. CHARTA SINAPIS (U. S. P., B. P.), mustard powder rendered adhesive by India-rubber, applied to sheets of paper and dried. The U. S. P. prepara- tion is formed from the black mustard, the B. P. from a mixture of the two. Oleum Sinapis Volatile (U. S. P., B. P.), derived from black mustard. Linimentum Sinapis (B. P.), formed from volatile oil of mustard, camphor and castor oil. Uses. Mustard is largely used as a condiment and to promote appetite, but is never prescribed for this purpose. In large quantities it causes violent irritation of the stomach and bowel, with vomiting, purging, acute pain and tenderness in the abdomen, and collapse. Mustard and warm water is a convenient emetic in emergencies, as in cases of poisoning. The plaster or leaf (charta) is the form in which it is generally used in therapeutics. It contains the glucoside, which is slowly decomposed by the ferment when the plaster is dipped in warm water for a few min- utes before application. Another popular application is the mustard poultice, in which powdered mustard is sprinkled on an ordinary poultice. Mustard is also added to baths occasionally when slight irritation and consequent congestion is desired over a large surface. For this purpose 24 teaspoonfuls of the dry powder are added for each gallon of water. In preparations of mustard it is important to avoid a temperature of over 60 C. (140 F.), as the ferment is de- stroyed above this. The plaster is left on the skin only for 15 to 30 minutes, when it is used as a rubefacient. III. Cantharidin Series. Another series of local irritants comprises n on- volatile substances, of which cantharidin is the best known. It is the anhydride of can- tharidic acid, which does not exist itself, but the salts of which are formed from cantharidin by the action of bases. Cantharidin is rep- resented by C 10 H 12 O 4 , and is a derivative of benzol. Its action on the central nervous system resembles, it is stated, that of the other members of that series, but is of no importance in comparison with its local irritant effects. Cantharidin is found in Spanish fly (Can- tharis vesicatoria, or Lytta vesicatoria) and in several allied species of Coleoptera (beetles). The irritant action of cantharidin and of many 90 ORGANIC SUBSTANCES ACTING LOCALLY. other drugs was formerly supposed to be due to its being an anhy- dride, but other anhydrides have no such specific action, and the can- tharidates are quite as powerful as cantharidin. Action. Applied to the skin, cantharidin produces redness, smarting and pain, followed very soon by small vesicles, which later coalesce into one large blister. This is much less painful than the vesication produced by mustard, because less of the irritant penetrates into the deeper tissues than in the case of the volatile mustard oil. If the blister be broken, however, and the unprotected dermis be allowed to come in contact with the irritant, violent inflammation with much pain, suppuration and even sloughing may follow. When large quantities of cantharidin are given internally, the same irritant action takes place along the alimentary tract. If taken in solution, blisters arise in the mouth and throat, and the pain and swelling in the oesophagus may be so acute as to prevent swallowing. The irritation of the stomach produces vomiting, followed by purging with excruciating pain in the abdomen, and all the symptoms of shock and collapse. Cantharidin is absorbed from the alimentary canal, and also to a less extent from the skin, but has no important action on the internal organs, with the exception of those by which it is eliminated. The heart is often accelerated in poisoning in animals, but has been slowed in some cases in man, while in others it was rapid and feeble. The respiration becomes rapid and dyspnoeic some time before death, and some confusion, deepening into coma and convulsions, may indicate a specific action on the central nervous system. Vomiting also occurs on subcutaneous injection, but the presence of ulceration of the stomach and of diarrhoea when it is absorbed from the skin, indicates that some of the poison is excreted into the alimentary tract, and the vomiting in these cases may therefore be of peripheral rather than of central origin. In the process of excretion, cantharidin has the same effects on the organs involved as on those of absorption. These effects are seen only in the genito-urinary tract in the vast majority of cases of poison- ing. Comparatively small quantities irritate the bladder, and cause a constant desire to micturate, with pain in doing so. In somewhat larger amount it sets up an acute nephritis with alburninuria, pain in the kidney region, and sometimes blood in the urine. The inflam- mation of the bladder and urethra produces intense pain and often priapism ; in women abortion is said to occur occasionally, and in both sexes the irritation may lead to increased sexual desire. The irritation of the kidneys by small doses increases their secretion, and cantharides was therefore considered a diuretic formerly. The tendency to produce nephritis renders it a dangerous internal remedy, however, and its diuretic power is quite insignificant in comparison with that of caffeine. Animals vary very considerably in the degree in which they react to cantharidin, the most noted example being the hedgehog, which is capable of surviving a dose of the poison sufficient to poison an adult SKIN IRRITANTS AND COUNTER-IRRITATION. 91 man. Fowls and rabbits also possess a high degree of congenital tolerance for this poison, although none of these is absolutely insus- ceptible to it. PREPARATIONS. Cantharis (U. S. P., B. P.), Spanish Fly, the dried beetle, Cantharis vesi- catoria. CERATUM CANTHARIDIS (U. S. P.). Collodium Cantharidatum (U. S. P.). Tinctura Cantharidis (U. S. P., B. P.), 0.1-0.3 c.c. (2-5 mins.). EMPLASTRUM CANTHARIDIS (B. P.). EMPLASTRUM CALEFACIENS (B. P.), warming plaster. Acetum Cantharidis (B. P.). Unguentum Cantharidis (B. P.). Collodium Vesicans (B. P.). Liquor Epispasticus (B. P.). Therapeutic Uses. Cantharides is at present used almost exclusively as a skin irritant, and more particularly as a vesicant. In the United States the cerate is generally used for this purpose, and is applied to the skin by means of adhesive plaster ; the corresponding preparation of the B. P. is the cantharides plaster. It is to be noted that, in order to produce actual blistering, the plaster has to remain in contact with the skin some 8-10 hours, but an equal effect may be achieved by re- placing the plaster by a hot poultice after 46 hours, when the skin irritation has reached the stage of redness. Cantharides is also used to cause rubefaction and commencing vesication (flying blister) ; this may be done by the use of these preparations, or by means of the warming plaster, B. P. Blistering collodion is used rarely in unmanageable cases in which there is a risk of the plaster being removed by the patient. The ointment is said to induce blistering sooner than the plaster. Cantharidin is liable to be absorbed from the skin, and its applica- tion is therefore avoided where there is any tendency to renal inflam- mation. Cantharides has been used not infrequently as an aphrodisiac, and several cases of poisoning have occurred from its administration for this purpose. In cattle it is largely employed to this end in some coun- tries, and in man it has undoubtedly similar effects in some cases through the irritation of the bladder and urethra, but its use for this purpose is always liable to produce nephritis. As an emmenagogue, cantharides has a certain popular reputation, which however has been shown to be unmerited, any influence which it may possess on the menstrual flow being quite insignificant, and probably due only to the irritation of the bladder and urethra. Cantharides has been advised internally in some forms of renal and vesical disease, but it is an exceedingly dangerous remedy in these conditions. In 1891, Liebreich proposed the treatment of tuberculous affections with can- tharidinates, in the belief that these would cause an inflammatory reaction around the diseased nodules, and would thus lead to their being destroyed or encapsuled in cicatricial tissue. It has not been determined whether 92 ORGANIC SUBSTANCES ACTING LOCALLY. cantharidin acts more powerfully on irritated tissues, such as those around the tubercles, but experience has shown that no benefit followed Liebreich's treatment, while in several cases severe nephritis resulted from the injection, and the method has therefore fallen into disuse. Cantharides is sometimes a constituent of hair washes, its irritant action on the skin being credited with causing a more rapid growth of the hair. In cases of Poisoning with cantharides, the stomach ought to be emptied as rapidly as possible by the stomach tube, provided the oesophagus allows of its passage. Demulcents and albuminous sub- stances are of use in slowing the absorption, but all oily or fatty bodies must be avoided, as they tend to dissolve the cantharidin and thus promote its absorption. Opium may be given for the pain, and if collapse sets in, the ordinary measures must be taken to combat it. Poison Ivy and Poison Oak. The commonest form of poisoning in the United States is the skin eruption produced by the leaves of poison ivy and poison oak (Rhus toxicodendron and venenata) which Pfaif has recently shown to be due to the presence of a neutral body, Toxi- codendrol, resembling closely the other members of this group. The effects of poison ivy can arise only from touching the plant, the poison- ous principle not being volatile. Very minute quantities of toxico- dendrol are sufficient to produce skin eruptions, however, y-flVo m &* causing distinct symptoms in susceptible persons. The popular belief that skin affections can be induced by approaching the plant, without actually touching it, is probably accounted for by the facts that the eruption may be very late in making its appearance, and that poison ivy is very frequently mistaken for harmless climbing plants. In the dermatitis from poison ivy, Pfaff recommends that the skin be washed and scrubbed with soap and water, or with alcohol, or a solution of lead acetate in alcohol. Ointments and oily liniments are to be avoided, as they dissolve the toxicodendrol and tend to spread it over the skin and thus produce further inflammation. For the same reason, the alcohol used to wash the part must be removed entirely, as the poisonous principle is soluble in it, while insoluble in water. Several little known substances may be classed along with cantharidin, which they resemble in their violently irritating effects on the skin and mucous membranes, and in being non-volatile. They are of little impor- tance in therapeutics, but not infrequently give rise to accidental poisoning, A number of the Ranunculaceae order are irritants, and this has been be- lieved to be due to their containing Anemonin, C 10 H 8 O 4 , which is closely con- nected to cantharidin in its chemical structure, but this has been disputed recently by Brondgeest, who asserts that this body is a convulsive poison. Noel and Lambert also state that anemonin is not the irritant contained in Anemone pulsatilla, which owes its irritant effects to some other more poisonous constituent. In Mezereum, Buchheim found an anhydride which he termed Mezerein, but Springenfeldt states that the action is due to an oil and to the acid which it contains, which resemble croton oil and crotonoleic acid in their effects. Cardol, found in the fruits of Anacardium occidentale and in Semecarpus anacardium, is a very powerful irritant, and has been used to a limited extent as a vesicant. Cardol is probably a mixture of a number of substanceSj but it is unknown to which of these it owes its activity. VEGETABLE PURGATIVES. 93 Euphorbin is said by Buchheim to be the irritant principle in the Euphorbia resin (Euphorbia resinifera, etc.), and to resemble cantharidin in its anhy- dride form, but the salts and the euphorbic acid which is formed from them by acids are inactive, while the salts of cantharidic acid are irritant, and cantharidin is reformed when they are broken up by acids. A very poisonous member of the Euphorbiaceee is the Manicheel tree, growing in the West Indies, and it apparently belongs to this series. Capsicum contains one or more non-volatile irritant substances which probably resemble the principles of this series more closely than any other. Capsicum is used in small quantities internally and has therefore been men- tioned along with the pepper series, but it is also used occasionally as a skin irritant. Pepper is also used as a rubefacient in domestic medicine. Chaulmoogra Oil, obtained from Gynocardia odorata, is apparently similar in character to the members of this group, although it is less irritant. It is used externally as an application to bruises, and both externally and internally in leprosy, although it is probably of little avail in this disease. It is said to owe its activity to Gynocardic acid, which it contains in combi- nation with glycerin. Croton oil is also used as a skin irritant, but will be treated of in connection with the purgatives (page 99). Many other plants possess irritant, poisonous properties, which would ap- parently entitle them to a place in this series, but so little is known of their active principles and of their effects, that they may be omitted for the present. PREPARATIONS. Mezereum (U. S. P.), Mezerei Cortex (B. P.), the bark of Daphne meze- reum and of other species. Fluidextractum Mezerei (U. S. P.). Mezereum is also contained in several of the sarsaparilla preparations (U. S. P.). Capsicum (U. S. P., B. P.). Emplastrum Capsici (U. S. P.). Unguentum Capsici (B. P.). (For the other preparations of Capsicum see page 73.) BIBLIOGRAPHY. Radecki. Inaug. Diss., Dorpat, 1866. Aufrecht. Centralbl. f. med. Wissensch., 1882, pp. 545, 849. Eliaschoff. Virchow's Arch., xciv., p. 323. Liebreich. Therap. Monatsheft, 1891, p. 169 ; 1892, p. 294 ; 1895, p. 167. Buchheim. Arch. d. Heilkunde, xiii., p. 1. Cot-nil. Comptes rendus de Facad., civ., p. 1875. Lewin. Deutsch. med. Woch., 1901, p. 184. Pfaff. Journ. of Exp. Med., ii., p. 181. ( Toxicodendrol. ) Springenfeldt. Inaug. Dis., Dorpat, 1890. (Mezereum.) Brondgeest. Schmidt's Jahrbuch, ccxx., p. 131. (Anemonin. ) Noel and Lambert. Arch, de Pharmacodynamique, iv., p. 169. (Pulsatilla and anemonin. ) VII. VEGETABLE PURGATIVES. Purgatives are drugs which are employed in medicine to evacuate the bowel of its contents. Many drugs produce evacuation in the course of their action, but have other effects of importance and are not included in this class. Thus the members of the preceding classes of skin irritants induce diarrhoea, but this is accompanied by irritation of the mouth, throat and stomach, and in many other forms of poisoning, diarrhoea is a prominent feature, but is accompanied by vomiting or 94 ORGANIC SUBSTANCES ACTING LOCALLY. some other symptom. The ideal purgative is devoid of any effects whatsoever, save in the intestine ; it passes through the stomach with- out materially deranging its function, and is not absorbed, or at any rate is absorbed so slowly that it has time to unfold its action through- out the intestine. The vegetable purgatives act through their irritant properties, which in some instances are elicited only by the action of the secretion of the intestines and of the neighboring glands. Thus some of the purgatives pass through the stomach in the form of bland, non-irritant compounds (castor oil), which are broken up by the diges- tive processes in the intestine, while others perhaps owe their activity in the intestine to their solution or suspension in the juices. Many classifications of the purgatives have been based on their effects, and some of the terms are still retained, such as aperient, ecco- protic, laxative, purgative, cholagogue, hydragogue, cathartic or drastic. But the effect of the purgatives is determined largely by the dose and by the condition of the intestine, so that a small dose may act as an ape- rient, laxative or eccoprotic, while a larger quantity of the same drug, or even the same dose in a more susceptible individual, may act as a drastic or hydragogue cathartic. It is, therefore, preferable to classify them according to their chemical nature as far as that is known, and in this way three classes may be formed, (1) purgative oils, (2) purga- tives of the anthracene series, (3) the jalapin and colocynthin group. Symptoms. In moderate doses the purgatives simply hasten the normal movements of the intestines, and the stool is of the ordinary ap- pearance and consistency (laxative, aperient, or eccoprotic action). In larger quantities they cause a more profuse evacuation than normally, and the stools, which are repeated at short intervals, are of a looser, more fluid consistency. Their action is accompanied by considerable pain and colic, and the hurried movements of the intestine are shown by the characteristic gurgling sounds. Large quantities of the more powerful purgatives may cause all the symptoms of acute enteritis ; the stools at first contain the ordinary faecal substances accompanied by more fluid than usual, but later consist largely of blood-stained mucous fluid with little or no resemblance to ordinary faeces. This violent purgation, which is not induced in therapeutics, is accompanied by pain and tenderness in the abdomen, and may induce shock, col- lapse and eventually death. Action. The origin of the fluid of the stools after purgatives has been much debated. According to many authors, they accelerate the passage of the intestinal contents so much that there is no time for the absorption of the fluid, and the faeces escape in the fluid con- dition in which they normally exist in the small intestine. Other in- vestigators hold that purgatives cause fluid to pass into the intestine, either by increasing the normal secretions, or by causing an inflam- matory exudate from the vessels. Both parties have founded, or at- tempted to confirm their statements by the results of the injection of the purgatives into loops of intestine isolated from the rest of the bowel. In these, some observers (Brunton, Roy) have found a larger VEGETABLE PURGATIVES. 95 accumulation of fluid after the injection of the purgatives, while others (Thiry, Radziejewski) found no more fluid after purgatives than after indifferent fluids. These contradictory results are probably due to the methods adopted, and the quantity of the drug injected. In small quantities, such as are used in the vast majority of cases in ther- apeutics, the irritation produced by the purgatives is probably only enough to accelerate peristalsis somewhat, and the fluid of the stools is drawn partly from the food and partly from the ordinary secretions of the digestive organs. In these cases the intestine is not actually inflamed, although some congestion may occur in it, as in all organs in a state of abnormal activity. On the other hand, when large quan- tities are ingested a true inflammation of the intestine occurs, mani- fested by increased movement, congestion, the exudation of fluid into the lumen of the bowel, and pain. In these cases the intestine pre- sents the usual signs of inflammation ; it is red and congested, and contains a muco-purulent fluid and often blood. The matter, therefore resolves itself into a question of dose ; if it be small, the fluid is not an exudate, if it be large the fluid is partly an inflammatory product. The stools following the administration of purgatives differ from the normal faeces in containing a larger proportion of water and also of soluble substances. In fact, they resemble rather the contents of the small intestine than the normal excreta, and contain bodies which would normally have been absorbed and utilized but which have been hurried through the bowel too rapidly to permit of their being taken up by the epithelium. The colic produced by purgatives is not due to the inflammation of the intestinal wall, but is probably explained by the more vigorous contractions of the walls of the bowel and the difficulty in forcing on hard faecal masses in the large intestine. The tenderness produced by large quantities of the purgatives, on the other hand, would seem to indicate inflammation. There is every reason to believe that purgation may be induced by reflexes arising from the stomach or skin, or from localized irritation of one part of the bowel ; and these reflexes, in some instances at least, must pass by way of the central nervous system. In the accel- erated peristalsis ordinarily induced by the purgatives, however, the central nervous system is probably not involved ; the irritation of the mucous membrane renders it more sensitive to the stimuli which it ordinarily receives from the contents, and the nervous impulses result- ing from these are transmitted to the intestinal nervous plexus and give rise to the reflex inhibition and contraction of the muscular coats by which the peristaltic movement is carried out. This action of the purgatives in increasing the irritability of the mucous membrane probably extends throughout the bowel, and the movements of both the small and the large intestine are accelerated. There is no reason to suppose that the food is retarded in its passage through the small bowel in constipation ; the delay takes place in the colon, and it is in 96 ORGANIC SUBSTANCES ACTING LOCALLY. increasing the irritability and removing the sluggishness of the latter that purgatives are beneficial. The action of the purgatives is generally considered purely local, and strictly analogous to that of the skin-irritants. The irritation of the epithelium and of the nerve-ends leads reflexly to increased activity of the deeper layers, which manifests itself in the bowel by contraction of the muscle, in the skin by hypersemia. But some of the purgatives seem to have a further action, which is of a more specific nature. Thus senna, aloin, frangnlin, and colocynthin cause evacuation of the bowel when injected subcutaneously or into the blood, podophyllum resin causes violent purging and vomiting when thus administered, and croton oil has long been rubbed on the skin in order to relieve con- stipation, and is found to cause intestinal inflammation and purging when injected intravenously. It has accordingly been suggested that these have a specific action on the bowel quite apart from their irri- tant effects ; but it is quite possible that their intestinal effects are here due to their excretion into the bowel, which has been shown to occur in several instances. Other irritants applied subcutaneously or intra- venously often produce similar effects on the alimentary canal. The interval which elapses between the administration of a purga- tive and its effects varies with the dose, and also with the individual drug. In ordinary therapeutic doses, evacuation of the bowels occurs in most cases in 5-10 hours, but if large quantities of the more pow- erful purges, such as jalap or croton oil, be given, the effects may be elicited in two hours. Aloes and podophyllum differ from the others in the length of the interval, catharsis rarely or never occurring ear- lier than 10-12 hours after their administration, and often only after 20-24 hours. The movement of the intestine induced by purgatives is accom- panied by an increase in the leucocytes of the blood similar to that observed in other forms of intestinal activity, e. g., during digestion. The effects of the purgatives vary greatly in different animals. Thus, the rabbit is very refractory to most of the series, and often is killed by intestinal irritation without any evacuation being produced. The frog is unaffected by quantities which would produce poisoning in man, while the dog and cat respond much more readily. It was formerly supposed that purgatives increased the secretion of bile, and certain of them, which were believed to have a special activity in this direction, were known as Cholagogues. It has been shown of recent years that none of them possesses any action on the secretion of bile, although they may increase its excretion by hurrying it through the intestine and preventing its reabsorption. On the other hand, the presence of bile in the intestine is a condition necessary to the activity of many of the purgatives. Thus Buchheim and Stadelmann found that in the absence of bile the following purgatives are either quite in- active or very much less powerful than usual podophyllum and podo- phyllotoxin, resin of jalap, convolvulin, resin of scammony, rhubarb, cathartic acid, and the sodium salt of gambogic acid. This is prob- VEGETABLE PURGATIVES. 97 ably due to some solvent action of the bile, for Stadelmann found that when soaps were given with some of these drugs their activity returned, and in other cases a comparatively slight modification of their chemical form was sufficient to restore their activity, even in the absence of either bile or soap. Analogous results have been observed from other causes than the absence of bile ; thus some of the pure principles of the purgatives are much less active than the crude drugs because the impurities of the latter alter their solubility. This alteration of the solubility may act in two ways : if the principle is rendered too soluble, it may be absorbed in the stomach and upper part of the bowel, and therefore fail to produce purgation ; on the other hand, it may be rendered so insoluble that it fails to come into intimate contact with the bowel wall, and therefore does not irritate it. The effects of such colloid substances as the bile and gums is to delay the absorption of soluble substances in the upper part of the bowel, and at the same time to keep the insoluble resins in suspension (Tappeiner). Few of the purgatives have any appreciable action after absorption, but general effects may be produced indirectly from their intestinal action. It is probable that reflexes are elicited by irritation of the bowel analogous to those discussed under skin irritants, but in addition, the congestion of the bowel produced by its activity must alter con- siderably the distribution of the blood in the body. The belief in the efficacy of a purge in congestion of the brain may thus be based on a true " revulsive " action ; for the dilation of the intestinal vessels must necessarily lessen the blood pressure and thereby the blood supply to the brain. The congestion of the intestine is accompanied by a similar condition in the other pelvic organs, and the purgatives therefore often cause congestion of the uterus, with excessive menstrual flow, or in the case of pregnant women, abortion. Lastly, a certain amount of fluid is withdrawn which would otherwise be excreted by the urine, which is found to be proportionately diminished in amount. 1. The Purgative Oils. Two very important members of the purgative series are Castor oil (Oleum Ricini), and Croton oil (Oleum Tiglii or Crotonis). 1 Castor oil consists almost entirely of an oil which resembles olive oil in most re- spects, but on saponification forms ricinoleic acid instead of oleic acid. This acid (C 17 H 32 (OH)COOH) differs from the fatty acids obtained from ordinary oils in being unsaturated and in containing a hydroxyl group. Castor oil is itself a bland, non-irritating fluid, but on passing into the intestine is decomposed by the digestive juices, and the ricinoleates thus formed are irritant and cause purgation. When the oil is saponified, and the free acid given by the mouth, the effects are quite different from those of the oil, for the taste is acrid and un- pleasant, and discomfort, nausea and vomiting may follow its in- 1 Another plant containing a purgative oil is the Jatropha curcas, which bears the Barbadoes nuts, or purging nuts. It is somewhat weaker in its action than croton oil, and is said to be often substituted for it in specimens of croton oil obtained from India, 7 98 ORGANIC SUBSTANCES ACTING LOCALLY. gestion from its irritant action on the stomach. The oil, on the other hand, has a bland, if unpleasant, taste, and produces no effects on the stomach. Several other esters of ricinoleic acid have been shown by Meyer to resemble the glycerin ester (castor oil) in their purgative effects. Croton oil is decomposed into glycerin and crotonoleic acid, of which little is known except that it is similar to ricinoleic acid from a chemical point of view. It differs from it in the fact that crotonoleic acid is a much more irritant body, and in that some acid is found free in the oil. This free acid renders croton oil irritant before it reaches the intestine, although the same process goes on here as in castor oil, and the croton oil therefore becomes more irritant than elsewhere. On the skin, and in the throat and stomach, croton oil exerts its irritant action, but these effects may be avoided while it continues to act as a purgative, if the free acid be removed. Croton oil then becomes bland and non-irritant, and can be distinguished from castor oil only by its more powerful pur- gative action. Castor oil is absorbed from the intestine and disappears in the tissues in the same way as an ordinary oil. Nothing is known with certainty of the fate of croton oil in the body, but it is not un- likely that it is excreted in part into the large intestine. Both croton oil and castor oil are borne in much larger quantities by animals than by man, and not infrequently the former causes acute enteritis without purgation. Castor oil may be given in very large quantities without producing any symptoms, save those of a mild laxative. Croton oil, on the other hand, acts as an irritant poison in any save the smallest doses, pro- ducing vomiting and violent purging with bloody stools, collapse and death. Castor oil is occasionally used as an emollient to the skin, and has been employed as a solvent for application to the eye, while croton oil has already been mentioned as a pustulant. The harmless nature of castor oil is shown by its use in China as an article of diet. It was formerly a matter of dispute whether croton oil causes the formation of pus when injected subcutaneous! y, or whether the presence of microbes is necessary, but it seems unquestionable now that croton oil alone is capable of producing this effect, provided that it contains free crotonoleic acid. The contradictory results obtained by observers may be explained by the fact that croton oil occasionally contains very little free acid, and that the mammalian tissues are unable to saponify the oil save in the presence of the intestinal ferments. In the frog these ferments are present in the tissues, or perhaps the latter are capable of breaking up the oil, for Hirschheydt found that the neutral oil caused inflammation and hemorrhages in various parts of the body. In the beans from which castor oil and croton oil are derived, toxalbumins are found, and these were at one time supposed to be the active principles of the oils. (See Ricin.) It has been shown, however, that the oils are en- tirely free from these poisons, and that their action is due solely to the acids of which they are glycerides. VEGETABLE PURGATIVES. 99 PREPARATIONS. OLEUM RICTNI (U. S. P., B. P.), a fixed oil expressed from the seed, or bean of Ricinus communis. Dose, 4-30 c.c. (1-8 fl. drs.). Mistura Olei Ricini (B. P.), made up with cinnamon and orange flower water by means of mucilage, 1-2 fl. oz. OLEUM TIGLII (U. S. P.), OLEUM CROTONIS (B. P.), a fixed oil expressed from the seed of Croton Tiglium. Dose, 0.02-0.05 c.c. (\-\ m.). Castor oil is difficult to take owing to its unpleasant taste. It may be given alone, in an emulsion flavored with sugar and some volatile oil, in wine, spirits or glycerin, or in flexible capsules. Croton oil is often given in a pill made up with bread crumb, or a single drop may be given on a lump of sugar or in solution in castor oil. 2. The Anthracene Purgatives. A number of purgatives, Rhubarb, Senna, Aloes and Frangula, owe their activity to the presence of irritant anthracene (C 14 H 10 ) compounds, only a few of which have been isolated. The chemical examination of these drugs is a matter of great difficulty, as they each contain several active principles which are very nearly related to each other, and some of which are undoubtedly the products of the decomposition of more complex bodies. In addition, several of the pure substances have been found to be less certain in their purgative action than the crude drugs, probably because the colloids in the latter aid in their solution. All those which have been completely isolated hitherto have proved to be derivatives of anthraquinone, CH CH CH CH CH CH c /\ c /\ /\ c HC/ \ HC/ \/ ' N ' CH HC - ' ' ' CH HC\ A. /\ yen ,/^ \ /\c/\c/\ HC/ NX Y | CH HC \/c\/c\/ CH CH CO CH C CH CH CH CH CO CH Anthracene. Anthraquinone. and some of the oxyanthraquinones seem to be widely distributed. Thus all the members of the group contain Emodin or trioxymethylanthraquinone, (C U H 4 (CH 3 )(OH) 3 O 2 ), and rhubarb and senna contain Chrysophanic acid or dioxymethylanthraquinone, (C U H 5 (CH 3 )(OH) 2 O 2 ), while a nearly related body has been found in Frangula. It is still undecided whether the emodin found in different drugs is identical or merely isomeric, and the same may be said in regard to curysophanic acid. In addition, a number of other an- thracene bodies occur in these purgatives, some of them combined with sugars to form glucosides, but little is known regarding them, and it seems likely that some may prove to be impure emodin. Acid glucosides have been found in rhubarb, senna (Cathartin or Cathartinic acid) and in cascara and frangula (Cathartin and Frangulin). In the different species of aloes several Aloins (Barbaloin from Barbadoes aloes, Socaloin from Socotrine aloes, etc.) have been isolated. Several of the pure principles have been used as purgatives, although they seem on the whole to be less certain in their effects than the crude drugs. Chrysophanic acid does not cause purgation, owing to its rapid absorption. Frangulin has given satisfactory results, and Cathartin has 100 ORGANIC SUBSTANCES ACTING LOCALLY. also been used experimentally, but is very liable to undergo decompo- sition. Aloin is less certain in its effects than aloes, and it seems to be indisputable that the crystalline aloin itself is inactive in the bowel, but is there changed under certain conditions to an amorphous compound which has irritant effects. This active substance can be prepared from aloin by boiling in water, and may be present in the amorphous resin left after the extraction of aloin. The purgative action of aloes is increased by the addition of small quantities of alkaline salts and of iron. The presence of bile in the intestine is not necessary to elicit the action of this group, except perhaps in the case of rhubarb ; enemata of aloes are inactive unless bile is injected with them, but Kohlstock found that the same results could be attained by dissolving aloin in glycerin. The latter produces evacuation when injected alone as an enema, it is true, but he used smaller quantities of it than are necessary for pur- gation, so that the role played by the bile is probably the same as that of glycerin a purely solvent one. The absorption of these bodies has not been satisfactorily determined in most cases. The urine is rendered yellow after rhubarb and senna, owing to the absorption and excretion of chrysophanic acid, but it is questionable whether the more active principles pass into the urine in appreciable amounts. When aloin is injected subcutaneously or intra- venously, it is excreted for the main part into the bowel, and there pro- duces irritation and catharsis. Cathartin and frangulin also act as purgatives when they are injected subcutaneously, probably because they are excreted into the bowel, although this has not as yet been investigated. The yellow pigment of the urine after rhubarb and senna becomes a purple red on the addition of alkalies * ; the milk and skin also are said to assume a yellowish tinge from the presence of chrysophanic acid. In the rabbit aloin seldom causes purgation, and is excreted by the kidney in considerable quantity, especially when injected hypoder- mically. In passing through this organ it causes marked irritation and epithelial necrosis, which often proves fatal in a few days. No irritation of the kidney occurs in man, the dog, or the cat after aloin. Rhubarb contains a considerable amount of tannic acid, which acts as an astringent and therefore tends to cause constipation after the evacuation of the bowels. It is not well tolerated in some cases, its administration being followed by nausea, headache and giddiness, more rarely by skin eruptions of different kinds. PREPARATIONS. U. S. P. Rheum, rhubarb, the root of Rheum officinale. EXTRACTUM RHEI, 0.3-0.6 G. (5-10 grs.). Fluidextractum Ehei, 1-2 c.c., (15-30 mins.). PILUL^E RHEI COMPOSITE (aloes, myrrh and oil of peppermint), 1-5 pills. PULVIS RHEI COMPOSITUS (Gregory's Powder) contains magnesia and ginger. Dose, 1-4 G. (20-60 grs.). Tinctura Rhei, 4-16 c.c. (1-4 fl. drs.). 1 For the reactions required to distinguish cliiysophanic acid in the urine from the pigment occurring in it after santonin, see page 122. 'VEGETABLE PURGATIVES. 101 Tinctura Rhei Aromatica (contains several volatile oils), 2-8 e.c. (-2 fl. drs.). Mistura Rhei et Sodse (contains bicarbonate of soda, ipecac, peppermint and glycerin), 10-100 c.c. (2 fl. drs.-3 oz.). A R OMA TI C US B. P. Rhei Radix, rhubarb root, the erect rhizome or so-called root of Rheum palmatum ; 3-10 grs. for repeated administration ; for a single ad- ministration, 15-30 grs. EXTRACTUM RHEI, 2-8 grs. PILULA RHEI COMPOSITA (contains rhubarb, Socotrine aloes, myrrh, and oil of peppermint), 4-8 grs. PULVIS RHEI COMPOSITUS (Gregory's Powder) contains rhubarb, light magnesia and ginger, 20-60 grs. TINCTURA RHEI COMPOSITA, formed from rhubarb, cardamom and cori- ander, |-1 fl. dr. for repeated administration ; 2-4 fl. drs. for a single ad- ministration. SYRTJPUS RHEI, -2 fl. drs. Infusum Rhei, 5 1 fl. oz. Liquor Rhei Concentrates, -1 fl. dr. U. S. P. Senna, the leaflets of Cassia acutifolia (Alexandria Senna), and of Cassia angustifolia (India Senna). CONFECTIO SENXJE contains senna, cassia fistula, tamarind, prune, fig, sugar, and oil of coriander, 48 G. (1-2 drs.). Fluidextractum Sennce, 4-8 c.c. (1-2 fl. drs.). INFUSUM SENNCE COMPOSITUM (Black Draught) contains senna, manna, magnesium sulphate and fennel, 60-120 c.c. (2-4 fl. oz.). SYRUPUS SENN.E, 4-16 c.c. (1-4 fl. drs.). Senna is also contained in the compound syrup of sarsaparilla and in the compound liquorice powder. Senna is often administered as a simple infusion, senna tea, a teaspoonful of the leaves being used in a cupful of water. B. P. Senna Alexandrina, the dried leaflets of Cassia acutifolia. Senna Indica, Tinnivelly senna, the dried leaflets of Cassia angustifolia. TINCTURA SENNJE COMPOSITA, formed from senna, raisins, caraway, and coriander, $-1 fl. dr. for repeated administration ; 2-4 fl. drs. for a single administration. SYRUPUS SENN^:, -2 fl. drs. Liquor Sennse Concentratus, -1 fl. dr. INFUSUM SENN^E, -1 fl. oz. ; as a draught, 2 fl. oz. MISTURA SENNCE COMPOSITA (Black Draught), formed from magnesium sulphate, liquorice, compound tincture of cardamom, aromatic spirit of ammonia, and infusion of senna, -2 fl. oz. CONFECTIO SENN.E, formed of senna, coriander, figs, tamarinds, cassia, prunes, liquorice, and sugar, 60-120 grs. U. S. P. Aloe, the inspissated juice of the leaves of several species of aloe. . Aloe Purificata, aloes from which insoluble impurities have been removed, 0.1-0.5G. (2-7 grs.). Aloinum, a neutral principle obtained from aloes, 0.05-0.2 G. (1-4 grs.). EXTRACTUM ALOES, 0.1-0.5 G. (2-7 grs.). PILULE ALOES, 1-5 pills. PILUL^E ALOES ET FERRI, 1-5 pills. Pilulce Aloes et Mastiches, 15 pills. Pilulce Aloes et Myrrhce, 15 pills. Pilulce Laxativce Compositce (aloin, strychnine, belladonna and ipecacuanha), 2 pills. TINCTURA ALOES, 2-8 c.c. (-2 fl. drs.). Tinctura Aloes, et Myrrhce, 2-8 c.c. (J-2 fl. drs.). Aloes is also contained in compound rhubarb pill, compound extract of colocynth, and compound tincture of benzoin. 102 ORGANIC SUBSTANCES ACTING LOCALLY. B. P. Aloe Barbadensis, the juice of Aloe vera and other species, Bar badoes Aloes or Curacoa Aloes, 2-5 grs. Aloe Socotrina, the juice of Aloe Perry i, Socotrine or Zanzibar Aloes. Aloinum, J-2 grs. EXTRACTUM ALOES, 1-4 grs. PILULA ALOES, 4-8 grs. Pilula Aloes Socotrinse, 4-8 grs. PILULA ALOES ET FERRI, 4-8 grs. PILULA ALOES ET ASAFETID^E, 4-8 grs. Pilula Aloes et Myrrhse, 4-8 grs. TINCTURA ALOES, J-l fl. dr. for repeated doses; fora single dose, l-2 fl. drs. Decoctum Aloes Compositum (aloes, myrrh, saffron, potassium carbonate, liquorice, compound tincture of cardamom), -2 fl. oz. Aloes is also contained in the compound extract of colocynth, compound colocynth pill, pill of colocynth and hyoscyamus, compound gamboge pill, compound tincture of benzoin and compound rhubarb pill. Some of the preparations are directed to be made from Socotrine, others from Barbadoes aloes, but there is really no difference in the effects. U. S. P. Frangula, Buckthorn, the bark of Rhamnus frangula, collected at least one year before being used. Fluidextractum Frangulce, 12 c.c. (1530 inins. ). U. S. P. Rhamnus Purshiana, Cascara sagrada, the bark of Rhamnus Purshiana. Extractum Rhamni Purshiance, 0. 25 G. (4 grs. ). Fluidextractum Rhamni Purshiance Aromaticum, 1 c.c. (15 mins.). FLUIDEXTRACTUM RHAMNI PURSHIANCE, 1 c.c. (15 mins.). B. P. Cascara Sagrada, the dried bark of Rhamnus Purshianus. Extractum Cascarce /Sagradce, 28 grs. EXTRACTUM CASCARA SAGRADA LIQUIDUM, -1 fl. dr. Syrupus Cascarce Sagradce Aromaticus, ^2 fl. drs. Two artificial compounds of oxyanthraquinone have recently been introduced under the names of purgatin and exodin. They are quite insoluble in water and tasteless but are decomposed in the intestine and act there like the other purgatives, to which they do not seem superior. Purgatin colors the urine red. Dose, 0.5-1.0 G. (8-15 grs.), in friable tablets or suspended in water. Of these numerous preparations, the most extensively prescribed are the pills. The fluid preparations have an unpleasant, bitter taste, and are therefore less used, unless when disguised by the addition of sugar or volatile oils. The syrups of rhubarb and senna are often admin- istered to children, and the confection of senna and the compound liquorice powder are also pleasant, easily taken preparations. The compound infusion or mixture of senna and the compound rhubarb powder are old and tried preparations, in which the virtues of the vegetable purgative are combined with those of a saline cathartic and antacid respectively ; they are both possessed of a harsh, unpleasant taste. Frangula is comparatively rarely used, but the fluid extract of cascara sagrada, which is practically identical with it, is a very popular remedy in habitual constipation. Pure Chrysophanic Acid is not adapted for use as a purgative, as even in doses of 0.3 G. it fails to increase the peristalsis. A compound of chryso- phanic acid, Chrysarobin (C 30 H 26 O 7 ), has found employment as an application in some forms of skin disease, especially in psoriasis, in which it is often of marked benefit. It is found in an impure form (Goa powder) in cavities in the Andira araroba, a tree growing in India and Brazil, and is isolated with VEGETABLE PURGATIVES. 103 comparative ease ; it forms chrysophanic acid when it is oxidized. Chrysa- robin is much more irritant than chrysophanic acid, and applied to the skin in a concentrated form, or in susceptible persons, causes itching, redness and swelling, less frequently papular or pustular eruptions ; the skin and cloth- ing are stained a reddish-brown color where it is applied. When swallowed, chrysarobin acts as a gastro-intestinal irritant, causing vomiting and purg- ing ; some of it is absorbed, and in its excretion by the kidneys causes in the rabbit nephritis with albumin and even blood in the urine. In man, slight albuminuria has been observed in some instances after its application to the skin ; in animals the epithelium of the renal tubules has been found to be necrosed, the glomeruli being less frequently affected. It was anticipated that it would undergo oxidation to chrysophanic acid in the body, and this is true for a part of that absorbed, but most of it passes through the tissues unchanged. Anthrarobin, an artificial derivative of alizarin, was advised at one time as a substitute for chrysarobin and chrysophanic acid in the treatment of psori- asis and other forms of skin disease, but its value has been disputed and it is comparatively seldom used now. Pyrogallol apparently acts in the same way in psoriasis as chrysarobin, and the effect has in each case been attrib- uted to the withdrawal of the oxygen from the diseased skin. Araroba (B. P.), or Goa powder, a substance found in cavities in the trunk of Andira araroba, free from fragments of wood, dried and powdered. Chrysarobinum (B. P.), a substance obtained from Araroba by extracting with hot chloroform, and evaporating. It consists for the most part of chrysarobin, but contains some chrysophanic acid. Unguentum Chrysarobini (B. P.), 4 per cent. Chrysarobin is used in skin diseases, especially in psoriasis, in which it is applied in ointment. Chrysophanic acid might be used also for this purpose were its isolation not attended with such expense. Some confusion has arisen from chrysarobin having been at first supposed to be chrysophanic acid. 3. The Jalapin and Colocynthin Group. The third group of the vegetable purgatives comprises a number of resinous glucosides and acids, whose more intimate chemical structure is unknown, though a number of them appear to be nearly related chemi- cally, so that it is possible that they all contain a common radicle like the members of the anthracene group. Jalap resin contains two anhydride glucosides, Convolvulin and Jalapin, the latter only in very small quantity. Scammony consists very largely of Jala- pin. Squirting cucumber contains a resin (elaterium), the active principle of which is Elaterin, another anhydride of which little is known. Podophyl- lum contains two isomeric glucosides, Podophyllotoxin and Picropodophyllin (C 23 H 24 O 9 ). Gamboge owes its activity to Cambogic acid, which, however, is insoluble, and seldom acts unless it is accompanied by the inactive bodies of the crude drug. Colocynthin is a glucoside occurring in the colocynth fruit, and forms Colocynthein and sugar when treated with acids. Colocvnthein is said to be even more irritant than Colocynthin. Bryony contains two gluco- sides, Bryonin and Bryonidin, of which the latter is the more active. Lep- tandra owes its activity to a resinous glucoside, Leptandrin, euonymus to a glucoside, Evonymin. Many other plants contain similar resinous purgative substances, and some of these are used as remedies to some extent, but so little is known of their properties and they are so seldom employed that they may be omitted here. 104 ORGANIC SUBSTANCES ACTING LOCALLY. Action. These substances are in general much more powerful than any of the other purgatives except croton oil, and are therefore classed along with the latter as the drastic purgatives or hydragogue cathar- tics. In small quantities they cause evacuation more rapidly than the anthracene purgatives, and in somewhat larger doses produce profuse watery stools with much pain and often tenesmus. In cases of poison- ing, the bowel undergoes acute inflammation, and blood is passed in the stools, which often contain shreds of epithelium from the walls. The irritant action is not confined to the bowel apparently for their administration is sometimes followed by uneasiness in the stomach, and occasionally by nausea and vomiting. On the other hand, mod- erate quantities are said not to induce colic so frequently as some of the anthracene purges. Several of these resinous purges are irritant to the skin and especially to the mucous membranes of the eye, nose and throat. Thus jalap, podophyl- lum and colocynthin all cause pain and irritation when they are applied to the nostrils in fine powder, and podophyllum has been used as a skin irri- tant. The presence of bile in the intestine increases the purgative action of al- most all these bodies, and in fact, seems absolutely necessary for the action of most of them. Some of them induce purgation when injected hypodermically, and this effect is not prevented by the absence of bile in the intestine. Podophyllotoxin and colocynthin cause purgation when injected subcu- taneously ; this is probably owing to their excretion into the bowel, as the former has been detected in the fa3ces after this method of administration. Podophyllotoxin causes glomerular nephritis and hemorrhages into various organs when administered hypodermically or intravenously in large quanti- ties, and when added to blood in a test-tube, it causes the formation of met- ha3moglobin in the corpuscles. It has been said to have a depressant action on the central nervous system, but this is probably a result of the shock and hemorrhage produced by its intestinal action. Colocynthin is said to cause renal inflammation when applied subcutaneously or taken internally, and even when the powder is inhaled during its manufacture. Jalapin and con- volvulin given by the mouth cannot be found in the faeces or urine, and are therefore supposed to undergo partial or complete oxidation in the body. Convolvulin is found in the urine, however, when it is injected intraven- ously, and no purgation follows this method of administration ; so that it is probable that convolvulin is decomposed in the bowel when it is adminis- tered internally. Euonymin has the same effect on the heart as digitalis, and will be men- tioned along with it, although it has a mild purgative action and is used chiefly as an aperient. PREPARATIONS. Colocynthis (IT. S. P.), colocynth, the fruit of Citrullus Colocynthis de- prived of its rind. Colocynthidis Pulpa (B. P.), the dried pulp of the fruit of Citrullus Colo- cynthis freed from seeds. Extractum Colocynthidis (U. S. P.), 0.1-0.3 G. (2-5 grs.). EXTRA CTUM COLOCYNTHIDIS COMPOSITUM (U. S. P., B. P.) (containing colocynth, aloes, scammony and cardamom), 0.2-1 G. (3-15 grs.). Colocynthin, 5-10 mg. (Not pharmacopceial.) VEGETABLE PURGATIVES. 105 PILULE CATHARTICS COMPOSITE (U. S. P.) (compound extract of colocynth, jalap, gamboge and calomel), I pill as laxative ; 3 as drastic purgative. PILULE CATHARTICS YEGETABILES (U. S. P.) (contain compound extract of colocynth, jalap, leptandra, podophyllum, hyoscyamus and oil of pepper- mint), 1 pill as laxative ; 3 as drastic purgative. PILULA COLOCYNTHIDIS CoMPOSiTA (B. P.) (colocynth, Barbadoes aloes, scammony resin, potassium sulphate and oil of cloves), 4-8 grs. PILULA COLOCYXTHIDIS ET HYOSCYAMI (B. P.), (compound pill of colo- cynth and extract of hyoscyamus), 4-8 grs. Podophyllum (U. S. P.) Podophylli Rhizoma (B. P.), the rhizome and roots of Podophyllum peltatum. Fluidextractum Podophylli (U. S. P.), 0.3-1 c.c. (5-15 mins.). RESINA PODOPHYLLI (U. S. P.), PODOPHYLLI RESINA (B. P.), 15-60 nigs. tt-1 g r -). Pilulce Podophylli, Belladonnas et Capsici (U. S. P.), 1 pill. TINCTURA PODOPHYLLI (B. P.), 5-15 mins. Podophyllin varies considerably in composition, and ought to be avoided. Podophyllotoxin. 5-10 mgs. Neither of these is pharmacopeia! . Jalapa (U. S. P., B. P.), the tuberous root of Ipomcea Jalapa. 0.3-1 G. (5-15 grs.). Extractum Jalapce (B. P.), 0.1-0.5 G. (2-8 grs.). EESINA JALAPS (U. S.P.), JALAPS RESINA (B. P.), 0.1-0.3 G. (2-5 grs.). PULVIS JALAPS COMPOSITUS (U. S. P., B. P.) contains jalap and bitar- trate of potash. 1-4 G. (15-60 grs.). Tinctura Jalapse (B. P.), i-1 fl. dr. Scammonium (U. S. P.), a resinous exudation from the living root of Con- volvulus Scammonia. Resina Scammonise (U. S. P.), 0.2-0.5 G. (3-8 grs.). B. P. Scammonise Radix, Scammony root, the dried root of Convolvulus Scammonia. Scammonium, a gum resin obtained from the scammony root,5-10 grs. Scammonise Resina, 3-8 grs. PILULA SCAMMONIS COMPOSITA (contains jalap and ginger), 4-8 grs. Pulvis Scammonii Compositus (contains jalap and ginger), 10-20 grs. Scammony is also contained in the compound colocynth preparations. Euonymus (U. S. P.), Euonymi Cortex (B. P.), Wahoo, the dried root- bark of Euonymus atropurpureus. Extractum Euonymi (U. S. P.), 0.05-0.2 G. (1-3 grs.). Extractum Euonymi Siccum (B. P.), 1-2 grs. Fluidextractum Euonymi (U. S. P.), 0.5 c.c. (8 mins.). Elaterinum (U. S. P., B. P.), C 20 H 28 O 5 , a neutral principle obtained from elaterium, a substance deposited by the juice of the fruit of Ecballium Ela- terium (squirting cucumber). 1-5 mgs. (fink g r -)- Trituratio Elaterini (U. S. P.) (one part elaterin in 9 parts sugar of milk), 15-60 mgs. (J-l gr.). Elaterium (B. P.), varies in strength, ^-\ gr. Pulvis Elaterini Compositus (B. P.) (one part elaterin in 39 parts milk sugar), 1-4 grs. Cambogia (U. S. P., B. P.), Gamboge, a gum resin obtained from Garcinia Hanburii. Pilula Cambogise Composita (B. P.) contains Barbadoes aloes and cinnamon, 4-8 grs. Leptandra (U. S. P.), Culver's root, the rhizome and roots of Veronica virginica. Extractum Leptandra (U. S. P.), 0.1-0.2 G. (2-4 grs.). Fluidextractum Leptandrce (U. S. P.), 2-4 c.c. (30-60 mins.). 106 ORGANIC SUBSTANCES ACTING LOCALLY. The resinous purgatives are generally administered in pill form ; very frequently two or more are combined in one pill, or they may be prescribed along with extract of belladonna or hyoscyamus, or with a drop of some carminative oil or resin, to prevent the pain and griping which often accompanies their action. The importance of these purga- tives is much less than it was formerly, and several of them are very seldom used ; the most important are colocynth, podophyllum, and jalap. In large doses they act rapidly, with the exception of podo- phyllum, which induces purgation very slowly (10-20 hours). Therapeutic Uses of the Purgatives. The purgatives are employed to cause evacuation of the bowel when for any reason its peristalsis is slow. In ordinary constipation of short standing, in which the peri- stalsis may merely seem somewhat more sluggish than usual, the milder laxatives are prescribed castor oil, senna, rhubarb, aloes, frangula, or cascara sagrada. The first two cause least disturbance of the bowel, but are disagreeable to take, and are less commonly prescribed for adults than rhubarb or cascara, or small doses of colocynth or podo- phyllum. In children or in debility in adults, senna and castor oil are frequently used however. In chronic constipation which cannot be controlled by hygienic measures, or by the use of a special dietary such as fruits, or coarse meal, and where the intestine has apparently taken on a sluggish habit, rhubarb, cascara, aloes, podophyllum, or colocynth may be ordered, but the saline cathartics often prove more satisfactory. Khubarb tends to cause some constipation after its laxative effects, but is often used in these cases, as it possesses some bitter stomachic action, which compen- sates for its astringent after-effects. This bitter action is often given to the other purgatives by the addition of gentian, nux vomica, or cinchona. In obstinate constipation, in which the bowel contains hard faecal masses, the milder purgatives often provoke griping without relieving the condition, and in these cases larger doses of colocynth, jalap, podophyllum, or croton oil are used, along with some of the ex- tracts of the atropine group or with a carminative oil. They may be prescribed along with some of the saline cathartics, as in the compound infusion of senna or the compound powder of jalap. Croton oil is used especially where the drug is required to be of small bulk and the administration is attended with special difficulty ; thus in unconsciousness or mania one or two drops may be given on sugar. In lead colic, croton oil is said to act more rapidly and effi- ciently than the others. In some forms of diarrhoea constant irritation seems to be kept up by the presence of irritants in the bowel, and the indications are the removal of these by a purge rather than the administration of astrin- gents. Castor oil, senna, and rhubarb are especially adapted for this purpose ; the two first because they increase the irritation of the bowel less than the others, the latter because of its subsequent astringent action. VEGETABLE PURGATIVES. 107 A purgative is often administered as a preliminary in the treatment of malaria, syphilis and other conditions, and seems to have beneficial effects, although these are difficult to explain. In the beginning of acute fevers also a purge is often useful, perhaps through the conges- tion of the bowel withdrawing the blood from the rest of the body, or through the removal of poisonous substances formed by the decompo- sition of the intestinal contents. In congestion of the brain a purga- tive is often administered with good effects, which may also be attributed to the accumulation of blood in the mesenteric circulation, and perhaps to some action analogous to counter-irritation of the skin. For these purposes a sharp purge is generally used, either croton oil or one of the jalapin and colocynthin series. The more powerful purgatives were formerly largely used to remove fluid from the body in cases of dropsy or oedema, and they were gener- ally prescribed along with the saline cathartics for this purpose. The violent action required is weakening, however, and while the fluid is withdrawn to a greater or less extent, the condition of the patient often undergoes little improvement, so that this measure is comparatively seldom used now. The congestion of the pelvic organs induced by these purges is not infrequently beneficial in cases of amenorrhoea. Aloes is almost exclu- sively used for this purpose, and is generally administered along with iron or with myrrh, which is credited with some special action on the genital organs. The purges act as intestinal disinfectants by removing the micro- organisms mechanically, though the vegetable purges are less used for this purpose than calomel. A purgative is administered to remove poisons in the intestine when they have passed beyond the stomach or when they are excreted into the bowel. Purgatives are contraindicated in conditions of acute intestinal irri- tation, and during menstruation and pregnancy, owing to the conges- tion of the pelvic organs, which may lead to an excessive flow in the one case and to abortion in the other ; aloes is especially dangerous in these conditions. In collapse, asthenia and anemia, powerful pur- gatives are contraindicated, owing to the irritation they produce. In hemorrhoids, aloes is often said to do harm by increasing the con- gestion of the rectum, and powerful purges are injurious from the straining they cause, but if constipation is present, a mild purgative is beneficial. In all those conditions, if a purgative is required, either castor oil, senna or rhubarb ought to be chosen. Eepeated attempts have been made to produce evacuation of the howels by substances injected subcutaneously. Hiller found colocynthin the best available for practical purposes, although aloin and cathartinic acid also acted efficiently. The injection is so painful, however, that it ought only to be had recourse to in exceptional circumstances. Dixon has recently suggested the use of apocodeine for this purpose (see Apomorphine). Another method by which the purgatives may be administered is in enema. 108 ORGANIC SUBSTANCES ACTING LOCALLY. The addition of purgatives, such as castor oil, and of bile to the ordinary enemata has been practised for many years, but Kohlstock has recently drawn attention to the use of purgatives by enema with only 1-3 teaspoonfuls of fluid. The large water enema, containing a pint or more of fluid, acts mainly by distending the bowel and thus setting up peristalsis, although the soaps, salt and other similar bodies, which are often added to it, may have an irritating effect in addition. In the small enema, however, distention plays no part, the movement being elicited by the irritant action of the drug. Kohlstock found that colocynthin (0.01-0.03 G.), aloin (0.4-0.5 G.), and cathartinic acid (0.6 G.) dissolved in glycerin caused purgation, colocynthin acting in -2 hrs., aloin in 2-12 hrs. and cathartinic acid in 1-6 hrs. The two latter were certain in their effects only in cases of moderate constipation. He attributes their action to absorption from the rectum. BIBLIOGRAPHY OF THE VEGETABLE PURGATIVES. Purgative action in general. Brunton. Practitioner, xii., p. 342. Siadelmann. Berliner klin. Woch., 1896, p. 181. Archiv f. exp. Path. u. Pharm., xxxvii., p. 352. Wood. Amer. Journ. of Med. Sciences, lx., p. 75. Hitter. Ztschr. f. klin. Med., iv., p. 481. Kohlstock. Charite-annalen, xvii., p. 283. Magnus. Ergebnisse der Physiologic, ii. (2), p. 661 (Literature.) Tappeiner. Arch, internat. de Pharmacodyn, x., p. 80. Dixon. Brit. Med. Journ., Oct. 18, 1902. Purgative oils. Buchheim. 1. c. Meyer. Arch. f. exp. Path. u. Pharm., xxviii., p. 145 ; xxxviii., p. 336. Robert u. Hirschheydt. Arb. des pharmak. Institutes zu Dorpat, iv., p. 5. Anthracene purgatives. ALOIN. Meyer. Arch. f. exp. Path. u. Pharm., xxviii., p. 186. Kohn. Berl. klin. Woch., 1882, p. 68. Murset. Archiv f. exp. Path. u. Pharm., xix., p. 310. Esselmont. Ibid., xliiL, p. 274. Tschirch. Bericht. d. deutsch. pharmaceut. Gesellsch., 1898, p. 174. SENNA. Kubly. Inaug. Diss., Dorpat, 1865. Stockman. Arch. f. exp. Path. u. Pharm., xix., p. 117. Gensz. Inaug. Diss., Dorpat, 1893. Vieth. Munch, med. Woch., 1901, No. 35. FRANGULA. Baeumker. Inaug. Diss., Gottingen, 1880. CHRYSAROBIN AND ANTHRAROBIN. Lewin u. Eosenthal Virch. Arch., Ixxxv., p. 118. Midler. Munch, med. Woch., 1896, p. 1221. Weyl. Pfliiger's Arch., xliii., p. 367. Koch. Inaug. Diss., Giessen, 1880. Marshall. Scottish Med. and Surg. Journ., May, 1902. (Purgatin.) Ebstein. Deutsch. med. Woch., 1904, p. 12. (Exodin..) Jalapin and Colocynthin Series. PODOPHYLLUM. Podwyssotzki. Arch. f. exp. Path. u. Pharm., xiii., p. 29. Neuberger. Ibid., xxviii., p. 32. Kiirsten. Archiv der Pharm., ccxxix., p. 220. ;;, Spindler. Inaug. Diss., Dorpat, 1893. JALAP. J. Muller. Inaug. Diss., Dorpat, 1885. Scher. Inaug. Diss., Dorpat, 1895 ; Virchow-Hirsch Janresber., 1895, p. 380. COLOCYNTH. Hagentorn. Inaug. Diss., Dorpat, 1857. ELATERIUM. Kb'hler. Virch. Arch., xlix., p. 408. BRYONIA. Mankowsky. Historische Studien a. d. pharmakol. Instit., Dorpat, ii., p. 143. VEGETABLE ASTRINGENTS TANNIC ACID SERIES. 109 VII. VEGETABLE ASTRINGENTS TANNIO ACID SERIES. A large number of vegetable substances owe their action to their containing tannin substances, while in many other preparations the ef- fect of more important constituents is modified by the presence of these widely distributed bodies. Tannic acid proper is derived from the oak gall, and seems to consist of an anhydride combination of gallic acid, into which it is very easily decomposed, probably according to the following equation : Tannic acid. Gallic acid. C 6 H 2 (OH) 3 CO 0(OH) 2 C 6 H 2 COOH + H 2 0^2C 6 H 2 (OH 3 )COOH. Gallic acid is formed from a large number of other bodies which closely resemble tannic acid in their general features, but are by no means identical with it. Their constitution is altogether unknown, but they possess a number of reactions in common and are generally classed together as the tannic acid substances. Some of them contain a sugar, and tannin or tannic acid is therefore sometimes said to be a glucoside. These bodies precipitate albumins, gelatins, alkaloids and some glucosides, and the salts of the heavy metals. The salts of iron form a bluish-black or greenish-black precipitate, and an attempt is sometimes made to divide the forms of tannic acid by this reaction, but they may be better indicated by their origin, as kinotannic acid from kino, catechutannic acid from catechu, etc. Action. The pharmacological effects of these bodies are due to their precipitating albumins and other proteids, and 'this reaction may therefore be described before their action in the body. If tannic acid solution be added to a neutral solution of albumin or gelatin, a white precipitate falls, which is entirely insoluble in water, but is soluble in excess of albumin or gelatin, in acetic or lactic acid, and in alkaline solutions. 1 Solutions of pepsin and of peptones are also precipitated by tannic acid unless in the presence of an acid. If pro- teid tannate be exposed to the action of the gastric juice it undergoes digestion and is dissolved in the same way as an ordinary coagulated proteid such as fibrin. During the process the tannic acid is set free from its combination apparently, and can precipitate undigested pro- teids, although it has no effect on the peptones in the acid medium. When a soluble tannate is formed by the addition of soda or potash to a tannic acid solution, the presence of proteids produces no precipitate, the affinities of the acid being satisfied by the alkali, and for the same reason the tannic acid precipitate is dissolved in the presence of alkalies. Tannic acid applied to animal tissue, as in the tanning of leather, causes a precipitation of the proteids, and the tissue becomes harder and tougher and tends to shrink together ; at the same time it has less tendency to undergo putrefactive changes and does not lose its flexi- 1 Some discrepancies in the accounts of different authors in regard to these reactions are perhaps due to variations in the amount of the neutral salts in their preparations. The account given by Lewin has been followed in the text. 110 ORGANIC SUBSTANCES ACTING LOCALLY. bility, as it would in drying. Strong solutions cause an immediate dense precipitate of the proteids on the surface and prevent the further penetration of the coagulating fluid, while the more dilute solutions are believed to penetrate more deeply and thus to cause a more complete precipitation of the proteids of the tissue. Tannic acid solutions have a harsh, bitter, "astringent" taste and produce in the mouth a feeling of constriction, dryness and rough- ness, along with a sense of stiffness in the movements of the tongue, and some loss of taste. These effects are due to the coagulation of the superficial layers of proteid both within and without the epithelium, which substitutes for the ordinary smooth surface a firmer, less even one, over which the tongue can no longer move easily. The feeling of constriction may, perhaps, be caused by an actual shrinking of the superficial layers of the epithelium, or may be due merely to the im- paired movements and sensation. The astringent feeling is continued in the throat as the solution is swallowed, and occasionally some discomfort or even nausea and vomit- ing are provoked by it, but as a general rule no such effects are observed. The stools are rendered harder and firmer by the administration of tannic acid, and constipation is often produced by it. In excess, tannic acid sometimes causes irritation of the intestine and diarrhoea, but beyond these symptoms of local irritation of the stomach and bowel, no effects arise from even enormous quantities of the drug. In the stomach, tannic acid combines with any proteid substance with which it may -come in contact and precipitates it, but as digestion pro- gresses, this combination is broken up, as the peptones do not combine with tannic acid in acid solution, and the astringent action is therefore exercised on the walls of the stomach and intestine. Ordinary quanti- ties cause the same superficial coagulation as in the mouth, but if large doses be given when the stomach and intestine are not protected by foodstuffs, a more complete coagulation of the mucous membrane takes place and the consequent irritation results in vomiting, and sometimes in diarrhoea. The increase in the consistency of the stools is probably due to the layer of coagulated proteid acting as a protective to the bowel, lessening its irritability and thus retarding its movements, so that there is longer time for the absorption of the fluid part of its contents, although this proceeds more slowly under tannic acid than normally (Gebhardt). Yeasts and microbes are precipitated by tannin, and this may tend to lessen the fermentations in the bowel in some cases, although some preparations of tannic acid which have been ex- amined in regard to this point have been found to have little or no effect on intestinal putrefaction. The local application of tannic acid causes a diminution of the se- cretions of glands, as has been demonstrated by Schutz. This is due to its effects upon the protoplasm of the secreting cells, which probably undergo the initial stages of coagulation. It was formerly believed that tannic acid caused constriction of the vessels of any part to which it was applied, but some doubt has been VEGETABLE ASTRINGENTS TANNIG ACID SERIES. Ill thrown on this by the experimental results obtained by Roseustirn and others. Heinz, the most recent writer on the subject, found that solutions of tannic acid of less strength than J per cent, caused con- striction of the meseuteric vessels of the frog or rabbit when applied directly, while more concentrated solutions caused transient constric- tion followed by dilation. Another local effect produced by tannic acid is seen in the cessation of the movements of the leucocytes in the tissues around the point of application and the arrest of their diapedesis through the walls of the vessels. When tannic acid comes in contact with blood in a test-tube it pre- cipitates the albumins, and when it is injected intravenously, the precip- itate formed leads to the formation of emboli. The alkaline tannates are generally believed to be entirely devoid of astringent effects, unless when the tannic acid is freed from the combination by the presence of an acid, but according to Heinz and Gottlieb the astringent action is only weakened and not entirely removed by combination with the alkalies. The fate of tannic acid in the body has given rise to some discussion. When it is taken internally a small proportion is sometimes eliminated by the bowel unchanged, but very often none is to be found in the stools ; traces are apparently absorbed and excreted in the urine as so- dium tannate in both man and animals, although some investigators have failed to detect these. When sodium tannate is administered in- ternally, a distinctly larger amount of it is absorbed and reappears in the urine. But much the greater part of the tannic acid is decomposed in the intestine into gallic acid, some of which often passes out in the stools, some in the urine. Only about one per cent, of the tannic acid swallowed reappears in the excretions, either as tannic or gallic acid ; the rest apparently undergoes complete oxidation in the tissues, for no further trace of it can be found. After tannic acid is administered, some tannic or gallic salt is present in the blood,- for iron salts give a darker color to it, but it is impossible to state whether this is tannin or a gallate, although in all probability it is the latter. According to Harnack, the gallic acid in the urine sometimes forms pyrogallol on standing, but this poisonous substance is not formed from tannic acid in the intestine or tissues. Tannic acid then does not exist in the tissues as such, but only in the form of traces of the gallate or tannate of soda, which are so small as to be devoid of astringent properties. Tannate of soda seems to have no action whatever, while gallic acid has no further properties than other weak acids. Theoretically, therefore, it is to be expected that the effects of tannic acid are limited to the point of application, and there is no evidence of any weight that it exercises any action after absorption. Lewin states that the muscles of the frog are altered in elasticity after the application of tannic acid subcutaneously, and an old observation is recorded in which the spleen was supposed to undergo contraction when tannic acid was administered, but the methods adopted render these observations worth- 112 ORGANIC SUBSTANCES ACTING LOCALLY. less. Tannic acid is often said to lessen the albuminuria in certain forms of Bright' s disease, but the only exact determinations which have been made in man showed that no such effect was present, and in Ribberts' experiments the animals were moribund when the improvement occurred, and no safe deductions can be made therefore. The urine is sometimes said to be diminished by tannic acid, but this statement is based on error. Last of all, tannic acid is said to lessen internal hemorrhage by contracting the vessels, but tannate of soda, the only form in which it can exist in the blood is entirely devoid of action. Gallic acid given by the mouth is absorbed and is excreted by the kidneys to some extent. Much of it disappears in the tissues, however, apparently by oxidation. The excretion of uric acid in the urine is considerably reduced by the administration of gallic acid. The numerous preparations of the pharmacopoeias which owe their activity to their containing tannic acid, differ from the pure drug in that the acid is only slowly dissolved out from the colloid mass, and there- fore acts less on the stomach and affects a greater length of intestine. PREPARATIONS. Acidum Tannicum (IT. S. P., B. P.), tannic acid, gallotannic acid or digallic acid (HC 14 H 9 O 9 ), an organic acid obtained from nut gall, 0.1-0.6 G. (2-10 grs.). GLYCERITUM ACIDI TANNICI (U. S. P.), GLYCERINUM ACIDI TANNICI (B. P.). Unguentum Acidi Tannici (U. S. P.). Collodium Stypticum (U. S. P.). Trochisci Acidi Tannici (U. S. P.), 0.06 G. (1 gr.) ; (B. P.), J gr. in ea'ch. Suppositoria Acidi Tannici (B. P.), 0.2 G. (3 grs.) in each. Acidum Gallicum (U. S. P., B. P.), gallic acid (HC 7 H 5 O 5 ), an organic acid usually prepared from tannic acid, has no astringent properties, nor, in fact any qualities which render it of value in medicine. GAMBIR (U. S. P.), an extract prepared from the wood of Ourouparia Gambir, 1G. (15 grs.). TINCTURA GAMBIR COMPOSITA (U. S. P.), (flavored with cinnamon), 4 c.c. (1 fl. dr.). Trochisci Gambir (U. S. P.). Gambir has been substituted for the Catechu of former editions of the Pharma- copoeia. Catechu (B. P.), an extract of the leaves and young shoots of Uncaria Gambier. TINCTURA CATECHU, $-1 fl. dr. Trochisci Catechu, each containing 0.065 G. (1 gr.) of catechu. Pulvis Catechu Compositus contains catechu, kino, krameria, cinnamon and nutmeg, 10-40 grs. Krameria (U. S. P.), Ehatany, the root of Krameria triandra and of Krameria Ixina, Kramerise Radix (B. P.), the dried root of Para Ehatany (Krameria argentea ?) or of Peruvian Rhatany (Krameria triandra). EXTRACTUM KRAMERIA (U. S. P., B. P.), 0.3-1 G. (5-15 grs.). Fluidextractum Kramerice (U. S. P.), 0.5-4 c.c. (10-60 mins.). Tinctura Kramerise (U. S. P., B. P.), 2-8 c.c. (J-2 fl. drs.). Syrupus Kramerise (U. S. P.), 2-10 c.c. Q-3 fl. drs.). Liquor Kramerise Concentratus (B. P.), -1 fl. dr. Infusum Kramerise (B. P.), J-l fl. oz. Trochisci Krameriae (U. S. P., B. P.). Trochiscus Kramerise. et Cocainse (B. P.), each containing ^ gr. of cocaine. VEGETABLE ASTRINGENTS T ANN 1C ACID SERIES. 113 Kino (U. S. P., B. P.), the inspissated juice of Pterocarpus Marsupium, 0.5-2 G. (10-30 grs.). TINCTURA KINO (U. S. P., B. P.), 2-8 c.c. (J-2 fl. drs.). PULVIS KINO COMPOSITUS (B. P.), contains 5 per cent, of opium, 5-20 grs. Hamamelidis Folia (U. S. P., B. P.), Witchhazel, the leaves of Hamamelis Virginiana, contains tannic acid, a volatile oil and a bitter. Hamamelidis Cortex (U. S. P., B. P.), the dried bark of Hamamelis Virgin- iana, witchhazel bark. Fluidextractum Hamamelidis Foliorum (U. S. P.), 2 c.c. (30 mins.). Aqua Hamamelidis (U. S. P.), 8 c.c. (2 fl. drs.). Extractum Hamamelidis Liquidum (B. P.), 5-15 mins. Liquor Hamamelidis (B. P.). Tinctura Hamamelidis (B. P.), J-l fl. dr. Unguentum Hamamelidis (B. P.). Haematoxylon (U. S. P.), Haematoxyli Lignum (B: P.), Logwood, the heart-wood of Hsematoxylon campechianum. Extractum Hsematoxyli (U. S. P.), 0.5-2 G. (10-30 grs.). Decoctum Hsematoxyli (B. P.), -2 fl. oz. Eucalypti G-ummi (B. P.), a ruby-colored exudation, or so-called red gum, from the bark of Eucalyptus rostrata and some other species of Eucalyptus. 2-5 grs. Trochiscus Eucalypti Gummi (B. P.), each containing 1 gr. of the gum. Geranium (U. S. P.), Cranesbill, the rhizome of Geranium maculatum. 1-2 G. (15-30 grs.). Fluidextractum Geranii (U. S. P.), 2-4 c.c. (30-60 mins.). Rubus (U. S. P.), Blackberry, the bark of the root of Kubus villosus, R. Canadensis and R. trivialis. Fluidextractum Rubi (U. S. P.), 2-8 c.c. (J-2 fl. drs.). Syrupus Rubi (U. S. P.), 2-8 c.c. (-2 fl. drs.). Galla (U. S. P., B. P.), Nut-gall, an excrescence on Quercus lusitonica (Quercus infectoria, B. P.), one of the oaks, caused by the punctures and ova of an insect, Cynips Galla3 tinctorise. Tinctura Gallve (U. S. P.), 2-12 c.c. Unguentum Gallte (U. S. P., B. P.). Unguentum Gallse cum Opio (B. P.) contains 7J per cent, of opium. Quercus (U. S. P.), white oak bark. 1 G. (15 grs.). Fluidextractum Quercus (U. S. P.), 1 c.c. (15 mins.). Rhus glabra (U. S. P.), the fruit of sumach. Fluidextractum Rhois Glabrce (U. S. P.). Several new preparations of tannic acid have been introduced into thera- peutics of late years, chiefly for use as intestinal astringents. Tannic acid itself is liable to produce irritation of the stomach, and to be decom- posed or absorbed to a large extent before it reaches the large intestine, and although the cruder preparations are less liable to these changes, even they are by no means devoid of disagreeable features. Meyer, therefore, introduced tannigen, or diacetyltannin, in which two of the original hydroxyl groups of the tannic acid are replaced by acetyl. This body is exceedingly insoluble in Avater, but is dissolved by alkalies. It was hoped that it would remain insol- uble in the stomach and only commence to act in the bowel, and Rost finds that after administration by the mouth, it occurs in the human faeces in small quantity as tannic acid, while in the cat it passes through the alimentary canal in part unchanged. At the same time the presence of gallic acid in the urine indicates that part of it undergoes the fate of tannic acid. Tannoform is a somewhat similar combination of tannic acid and formaldehyde, while tannopin is a still more recent and untried member of the series. Both tannigen and tannoform are astringent in the mouth and stomach, but reach the bowel owing to their insolubility. The tannalbin of Gottleib, on the other hand, is a combination of tannic acid and albumen, dried at such a 114 ORGANIC SUBSTANCES ACTING LOCALLY. temperature as to prevent the action of the gastric juice upon it, but capable of being broken up by the more powerful pancreatic fluids. It is entirely insoluble and is not astringent until digested in the bowel, so that it has no irritant action on the stomach and is tasteless. Host found tannalbin and tannic acid in the fa3ces of the cat after its administration, while only gallic acid occurs in the stools and urine in man, showing that in the latter the whole of the tannalbin administered is decomposed in its passage through the alimentary canal. Tannocol is a combination of tannic acid and gelatin, resembling tannalbin in most respects. TANNIGEN, 0.5-2 G. (10-30 grs.), in powder. TANNALBIN, 0.5-2 G. (10-30 grs.), in powder. Several combinations of gallic acid have been introduced of late years as astringents. They can have no such effect, however, and must be regarded as additions to the group of inert protective powders, which is already rep- resented in overabundance in therapeutics. Therapeutic Uses. The preparations of tannic acid ought to be used for their local effects exclusively. They are applied externally in cases of excessive secretion, as in local sweating or weeping ulcers, and occasionally to harden the skin. For this purpose tannic acid may be used in solution in water, or in the form of the glycerite or ointment, or some other fluid preparation may be preferred. The styptic collodion may also be employed for this purpose, the evaporation of the solvent leaving the surface covered with a thin layer of collodion impregnated with tannic acid. Tannic acid is used as a mouth wash in cases of swol- len gums, or relaxed throat, and may here be prescribed in a flavored solution or in the form of lozenges, of which the pharmacopeia offers a choice. In certain forms of diarrhoea the astringent action of tannic acid is of considerable value, and occasionally when such drugs as cod-liver oil cause diarrhoea, tannic acid prevents this action without hindering their general effects. The pure drug is seldom used in these cases, as it is liable to derange the stomach and to form compounds with the albumins before it reaches the bowel, and catechu, krameria or kino is accordingly prescribed, either in the form of pills or in fluid preparations. Possibly all of these may be replaced in the early future by such artificial compounds as tannigen or tannalbin. Tannic acid stops hemorrhage by precipitating the proteids, when it comes into immediate contact with the bleeding point, but it is not of so much value for this purpose as some of the metallic astringents. When the bleeding point can be reached directly, the pure acid is used, but for hemorrhage of the intestine or stomach one of the extracts is preferred. Large enemata containing tannic acid have been advised in cholera, dysentery and similar conditions. In cases of poisoning with metals and alkaloids, tannic acid is often used to cause their precipitation in the stomach, but the tannate formed must be removed at once, as it is gradually dissolved in the digestive fluids. The administration of tannic acid is therefore only a tem- porary expedient to allow of active measures being taken to empty the stomach. ANTHELMINTICS. 1 15 Some individuals are peculiarly susceptible to the action of tannic acid, which induces local irritation and inflammation wherever it is applied in these cases. BlBLIOGKAPHY. Hennig. Arch. f. physiol. Heilkunde, xii., p. 599. Rosenstim. Rossbach's Pharmakologische Untersuchungen, ii., p. 78. Lewin. Virchow's Archiv, Ixxxi., p. 74. Deutsch. med. Woch., 1904, p. 803. Stockman. Brit. Med. Journ., 1886, ii., p. 1077. Arch. f. exp. Path. u. Pharm., xi., p. 147. Morner. Ztschr. f. phys. Chera., xvi., p. 255. Heinz. Virchow's Arch., cxvi., p. 220. Schiitz. Arch. f. exp. Path. u. Pharm., xxvii., p. 202. Meyer. Deutsch. med. Woch., 1894, p. 626. Gottleib. Ibid., 1896, p. 163. Host. Arch. f. exp. Path. u. Pharm., xxxviii., p. 346. Centrabl. f. Physiol., xii., p. 258. Harnack. Zeitschr. f. physiolog. Chemie, xxiv., p. 115. Ftatow. Deutsch. med. woch. Therap. Beilag., 1899, p. 37. Straub. Arch. f. exp. Path. u. Pharm., xlii., p. 1. Gebhart. Deutsch. Arch. f. klin. Med., Ixvi., p. 585. IX. ANTHELMINTICS. Anthelmintics are drugs which are used to kill or remove intestinal worms. They possess no such mutual resemblances in their effects as are met with in the purgatives, and their arrangement in a class is therefore artificial ; at the same time, they have no marked affinities with other groups, and it is convenient to have those bodies which are used exclusively for this purpose placed together. In order to possess any value as an anthelmintic, a drug must, of course, act more strongly on the parasite than on the host, and this more intense effect may be attained either by a specific action on the para- site, or by the drug failing to be absorbed from the alimentary canal. As a matter of fact, the anthelmintics, with the possible exception of pelletierine, have no such specific action, and their use is rendered pos- sible only by their slow absorption. In this point they resemble the purgatives, from which they differ, however, in causing little or no irritation in the stomach or bowel. Anthelmintics are often divided into vermicides and vermifuges, according as they kill or merely cause the expulsion of the worm, but as this is determined largely by the quantity which comes in contact with the parasite and the rapidity with which the bowel is evacuated, the distinction is imaginary. Before the administration of an anthelmintic, the bowel ought to be emptied of its contents as far as possible by a light, easily digested diet and a laxative, and a brisk purge ought to follow some hours later, in order to remove the dead or stupefied worm. The anthel- mintic is often prescribed along with a purge. A number of drugs belonging to other groups are used occasionally as anthelmintics. Thus several of the volatile oils tansy, turpentine have some reputation ; and chloroform is also administered occasionally by the mouth for its action on the parasites, but, like jt-he volatile oils, 116 ORGANIC SUBSTANCES ACTING LOCALLY. is apt to produce gastric and intestinal irritation. The less easily absorbed antiseptics, such as naphthol, have been used with good results, and thymol is regarded as a specific in cases of uncinariasis. Large enemata of salt solution, or of infusion of quassia, are thrown into the rectum when the worms infest the large intestines. The anthelmintics proper may be divided into those which are used for tapeworm, of which male fern, cusso and pomegranate are the most largely used, and those for the round worm of which santonin is the chief. Besides these, an enormous number of substances have been used popularly as anthelmintics, but have not been shown to have any advantages over those more generally adopted in medical practice. Male Fern (Aspidium Filix-mas). A number of ferns contain bodies which present considerable re- semblance to each other from a chemical as well as from a pharma- cological point of view, and which may therefore be classed together, at any rate until further information is available regarding them. The best known of these is the male fern (Aspidium Filix-mas). The active constituent of this remedy was supposed to be Filicic Acid by Poulsson, but Boehm has found a series of neutral and acid bodies present in much larger amount Aspidin, Aspidinin, Flavaspidic Acid, Albaspidin and Aspidinol of which aspidin is contained in largest quantity in the root and is the most important, although aspidinin is also highly poisonous. A number of these constituents have been shown to be derivatives of phloroglucin, and it is probable that they are all closely related. The therapeutic and toxicological effects of the male fern are to be attributed then to aspidin, aspidinin, and filicic acid. * Action. The extract or oleoresin of male fern, which is the only om of these plants used in regular medicine, as a general rule passes through the bowel without causing any symptoms whatever. The quantity of active substance dissolved, while sufficient to destroy the parasite, is too small to produce any effects on the host, and escapes with the other contents of the bowel, or if absorbed does not cause any symptoms. In some cases, however, where large quantities are admin- istered, or where some unknown conditions favor the absorption and retention of an unusually large amount of the active constituents, grave and even fatal symptoms may supervene. These consist in vomiting and purging, with acute pain in the abdomen, muscular weakness confusion and somnolence, with occasional twitching of the muscles, 01 slight convulsive movements, collapse, coma and death. The stomach 1 Nearly related bodies have been found in Aspidium athamanticum (Uncomocomo), which contains two forms of Pannic Acid, and in Aspidium spinulosum, while smallei quantities of acids occur in a large number of ferns. Several of these ferns enjoy a reputation as anthelminics for tapeworm, and their virtues are generally considered due to these bodies, although Kobert maintains that it is partly to be ascribed to the fixed or volatile oils which accompany them. ANTHELMINTICS. 117 and intestine are found congested and swollen, and sometimes covered with small ecchymoses. In some cases icterus has been observed to follow the administration of male fern, probably from the duodenal catarrh, but possibly from destruction of the red blood cells, the num- ber of which has been found to be diminished in some instances (Georgiewsky). In other cases permanent or temporary blindness has resulted from neuritis and subsequent atrophy of the optic nerve. In the rabbit, filicic acid produces very similar symptoms. The congestion of the stomach and intestine is evidently due to the local irritation produced by the poison, while the other symptoms point to changes induced in the central nervous system. It would seem probable that the spinal cord is affected in the same way as by strychnine, for the reflex excitability is dis- tinctly increased. The higher parts of the central nervous system seem to be depressed, and the paralysis of the respiratory centre is the cause of death, although the heart is also weakened by filicic acid. Inflammation of the kidney is said by some authors to occur, and in some cases Poulsson found evidence of glycuronic acid in the urine. In the frog, a mixture of depression and stimulation of the central nervous system is produced by filicic acid, along with a distinct diminution in the strength of the skeletal muscles and the heart. Aspidin injected into the frog causes dyspnoea followed by paralysis of the spontaneous and respiratory movements ; fibrillary twitching of the muscles sets in after some time and is succeeded by convulsive movements or tonic spasms, which indicate an increased activity of the reflexes of the spinal cord. The heart is depressed and eventually paralyzed, and the peripheral muscles are also weakened. The muscular tissue of the invertebrates is more powerfully affected by the constituents of male fern and Straub attributes its action on the tapeworm to its paralyzing muscle. Mammals do not seem to be affected by aspidin injected hypodermically or administered by the mouth, but when it is introduced directly into the blood vessels, it proves fatal by paralyzing the respiratory centre. Aspidinin induces very similar symptoms in the frog, while the other constituents are less active. The blindness which has been observed in some cases of male fern poison- ing has also been produced in dogs ; it occurs chiefly in young, weakly and anaemic individuals. Pannic acid differs from filicic chiefly in its acting more strongly on muscle and less on the central nervous system of the frog. PREPAKATIONS. Aspidium (U.S. P.), Male fern, the rhizome of Dryopteris Filix-mas and of Dryopteris marginalis, Filix Mas (B. P.), Male fern, the rhizome of Aspidium Filix-mas. OLEORESINA ASPTDII (U. S. P.), 2-8 c.c. (-2 fl. drs.). EXTRACTUM FILICTS LIQUIDUM (B. P.), 45-90 mins. The oleoresin (U. S. P.) and the liquid extract (B. P.) are practically iden- tical in composition. Therapeutic Uses. Male fern is used exclusively in the treatment of tapeworm and of Anchylostomum duodenale. Previous to its admin- istration the bowel ought to be emptied, as far as possible, by a moder- ately light diet for one or two days and, where necessary, by a purgative. The oleoresin, or liquid extract, is then to be administered in the form of pills or enclosed in a capsule or suspended in mucilage, and another purgative is required some 6-12 hours later. In case the parasite fails to be dislodged, several days ought to be allowed to elapse before a 118 ORGANIC SUBSTANCES ACTING LOCALLY. second dose is given. Poulsson recommends that oily substances be avoided during the "cure," as they dissolve the filicic acid, and thus promote its absorption. It is impossible to estimate the importance of this fact since Boehm has discovered the other active constituents, but it is certainly suggestive that in many cases of poisoning with male fern castor oil had been given along with it or soon after. Marked anaemia, general debility, and chronic alcoholism seem to predispose to male-fern poisoning, and the drug is accordingly to be used with care in these conditions. BIBLIOGRAPHY. Poulsson. Arch. f. exp. Path. u. Pharm., xxix., p. 1 ; xxxv., p. 97; xli., p. 246. Robert. Therap. Monatsheft, 1893, p. 136. Birch-Hirschfeld. Graefe's Arch. f. Ophthalmologie, 1., p. 225. Masius. Bull de 1'Ac. de Med. de Belg., 29 June, 1895. Georgiewsky. Ziegler's Beitriige, xxiv., p. 1.' Boehm. Arch. f. exp. Path. u. Pharm., xxxv., p. 1 ; xxxviii., p. 35. Straub. Ibid., xlviii., p. 1. Walko. Deutsch. Arch. f. klin. Med., Ixiii., p. 348. Cusso. Cusso, or Kousso, contains a neutral body, Kosotoxin, which is sol- uble in alcohol and in alkaline fluids, but is insoluble in water ; it is probably nearly related to the active constituents of male fern, which it resembles somewhat in its pharmacological action. Cusso has a bitter, somewhat astringent taste, and sometimes causes nausea and vomiting and some looseness of the bowels. In rare cases prostration and collapse, with irregularity of the pulse, are said to have occurred from its use. In the frog, kosotoxin paralyzes the nerve ends like curara, and has a specific action on the striped muscular tissue, which it weakens and eventually paralyzes. The heart muscle undergoes similar changes. In mammals the muscular action is well developed, but is accompanied by some stimulation of the medullary centres, indicated by rapid, dyspnoeic breath- ing, salivation and vomiting. The stools are often fluid, and the urine is increased in amount. When it is injected directly into the circulation, some convulsive movements are often observed, and the heart is weakened and paralyzed. Kosotoxin seems to be a general protoplasm poison, as is indi- cated by its action on muscle, and by its retarding the growth of yeast. PREPARATIONS. Cusso (U. S. P., B. P.) (Kousso or Brayera), the female inflorescence of Hagenia Abyssinica (Brayera anthelmintica). Cusso is generally given" by suspending 15 G. ( oz.) of the powdered flowers in water. Kosotoxin has not yet been prescribed for therapeutic purposes. The usual preliminary treatment ought to be instituted, but no purge is required after Cusso as a general rule. Therapeutic Uses. Cusso is used exclusively as an anthelmintic in cases of tapeworm. BIBLIOGRAPHY. Leichsenring. Arch. d. Pharm., ccxxxii., p. 50. Handmann. Arch. f. exp. Path. u. Pharm., xxxvi., p. 138. ANTHELMINTICS. 119 Granatum. The bark of the pomegranate contains a very large amount of tannic acid (20-25 per cent.), along with numerous alkaloids, of which Pdletierine, or Punirine, and Isopunicine alone are active in ordinary doses. All the pomegranate alkaloids are closely related chemically to each other and to tropine (see atropine). None of them can be classed among the more active poisons as far as man and the higher animals are concerned. In man, large doses cause heaviness, confusion, giddiness and very marked weakness of the limbs. The consciousness is but little affected, but the sight is often dim and uncertain, and in one case complete blindness persisted for several days. Occasionally nausea and discom- fort in the abdomen are complained of, and more rarely vomiting, tremors and cramps of the leg muscles are produced ; the gastric symp- toms are perhaps due to the large quantity of tannic acid in the drug rather than to the alkaloids. In the frog and in most mammals, pelletierine causes a distinct increase in the reflex irritability of the spinal cord and medulla oblongata, along with some depression of the higher divisions of the central nervous system. Very large doses weaken or paralyze the conductivity of the nerve plates in the frog, like curara. The heart muscle is also acted on and its pulsations are slowed in the frog, although they may be temporarily augmented in force. Pelletierine and isopunicine have a specific action on tapeworms, for Schroeder found that a solution of one part in 10,000 was suffi- cient to kill them in ten minutes, while a stronger solution had prac- tically no effect upon other intestinal worms. PREPARATIONS. Granatum (U. S. P.), Granati Cortex (B. P.), Pomegranate bark, the bark of the stem and root of Punica Granatum. Decoctum Granati Corticis (B. P.), |-2 fl. oz. Fluidextractum Granati (U. S. P.), 2 c.c. (30 mins.). PelletierincB Tatinas (U. S. P.), a mixture in varying proportions of the tan- nates of four alkaloids (punicine, isopunicine, inethylpunicine and pseudo- punicine), obtained from the pomegranate. Dose, 0.25 G. (4 grs.). Granatum is used as a decoction formed of 30-60 G. (1-2 oz.) in 250 c.c. of water ( pt.), to be taken in two parts, at an interval of one hour. The bark ought to be as fresh as possible, as the alkaloids decompose on keeping. The presence of large quantities of tannic acid renders the decoction very unpleasant to the taste, and flavoring substances are therefore generally prescribed with it, or pelletierine tannate may be ordered. Therapeutic Uses. Granatum is used exclusively as an anthelmintic. The preliminary treatment is the same as that given under aspidium, and a purge ought to be given J-2 hours after the decoction. BIBLIOGRAPHY. Dujardin-Beaumetz. Bull, de Therap., xcviii., p. 433. Eerenger-Feraud. Ibid., xcvii., pp. 8, 337, 391. v. Schroeder. Arch. f. exp. Path. u. Pharm., xviii., p. 381, and xix., p. 290. Henze. Pfliigei-'s Arch., xcii., p. 464. 120 ORGANIC SUBSTANCES ACTING LOCALLY. Kamala is a reddish-brown powder which consists of the minute glands and hairs obtained from the surface of the fruits of Mallotus Philippensis. It con- tains two or more substances which have been termed Kamalin, Rottlerin or Mal- lotoxin, and which are probably neutral bodies like kosotoxin, but it is not known which of these is the active constituent. Kamala is used in cases of tapeworm in doses of 2-8 G. (30 grs.-| oz.) suspended in water. It acts as an intestinal irritant, causing purging and, more rarely, nausea and vomiting. No purge is necessary, therefore, after the powder. An alcoholic tincture of kamala has been found quite as efficient as the powder. Pepo (pumpkin seed) contains a fixed oil and resin, and the latter seems to have considerable power as an anthelmintic, although this is disputed by some authorities. No symptoms are produced by very large quantities of the powdered seeds. Pepo (IT. S. P.), the seed of Cucurbita pepo, Pumpkin seed, is generally administered in doses of 60-120 G. (2-4 oz.), the powdered seed being sus- pended in an emulsion or in sugar or honey. Pumpkin seed has no laxa- tive effect and its administration is, therefore, to be followed by a purge. The resin has been used with good effects in some cases. Santonin. Santonin (C 15 H 18 O 3 ) is an anhydride or lactone of santoninic acid, which is formed from it by the action of alkalies, and is a derivative of naphtalene. It occurs in Artemisia pauciflora along with a nearly related body (artemisin) and a volatile oil (cineol). Santonin is very insoluble in water, but is dissolved by alkalies, with which it forms sautoninates. Action. Owing to its insolubility in water, santonin has only a slightly bitter taste in the mouth. It is partially dissolved in the stomach and absorbed, but enough passes into the bowel to effect the removal of some forms of intestinal worms. Under special conditions it is possible that the greater part of the santonin may be absorbed in the stomach, however, and general poisoning results without the para- sites being affected. A certain amount of absorption occurs in every case, as is shown by the disorders of color vision and by the yellow coloration of the urine. At first objects appear of a bluish color to the patient, but this aberration is of comparatively short duration and may in fact pass unnoticed. It is followed by a much longer period of " yellow sight " or xanthopsia, during which objects that are brightly illuminated seem to have a yellow tinge, blue seems green, and violet is indistinct, although in dimmer lights the violet may still predomi- nate. In severe poisoning the appreciation of the darker colors becomes very imperfect, and violet and even blue may fail to be distinguished from black. In general the violet end of the spectrum is shortened, while the yellow impresses the retina more vividly than normally. Sometimes " hallucinations " of vision are said to occur under santonin, although these seem to be unimportant ; thus one observer saw green globes on a violet background whenever he closed his eyes. These aberrations of sight are the most generally observed symptoms produced by santonin, but in some cases the sense of taste and smell, and more rarely the hearing, are also deranged. These symptoms all pass off in the course of a few hours, a second stage of " violet sight " occasionally intervening before complete recovery. ANTHELMINTICS. 121 The symptoms produced by the absorption of large quantities of santonin are so uniform in man and the other mammals that it is suffi- cient to enumerate those observed in experiments on the dog. The first distinct effects are generally twitching of the muscles of the head, frequently beginning on one side. These are followed by roll- ing of the eyes, grinding of the teeth, flexion and extension of the neck and rotation of the head from side to side, later by regular epi- leptiform convulsions in which the animal is first thrown into opistho- tonos and then into clonic spasms of the limbs and trunk. These are interrupted by intervals of repose during which a curious momen- tary contraction of all the muscles of the body is often noticed. Dur- ing the convulsive seizures the respiration is irregular and insufficient, and in fatal cases it fails to return after the convulsion passes off, and the animal dies of asphyxia. In man, some confusion, nausea and vomiting occasionally occur after quantities which are too small to produce convulsions, and in several cases aphasia has been observed. In frogs, convulsions are produced by santonin as in mammals, but they are preceded by a prolonged stage of depression, \vhich is entirely absent in the higher animals. These symptoms manifestly point to changes in the central nervous system. The xanthopsia is generally referred to a specific action on the retina, though some hold that the central apparatus of vision in the brain is the seat of the action. 1 The condition has been ascribed to a preliminary stimulation and subsequent depression of the sense organs for the perception of the violet and eventually of the blue rays of the spectrum, or more precisely to some obstruction to the regener- ation of the substance in the retina which normally appreciates violet rays (Filehne). The clonic nature of the convulsions at once points to an affection of the brain rather than of the cord, but some dis- cussion has arisen as to how far the cortical areas are involved and how far the symptoms may be explained by stimulation of the basal ganglia. The latest investigators have come to the conclusion that the epileptiform convulsions are due for the main part to the stimulation of the cortex, while the sudden contractions observed in the intervals of repose are ascribed to increased activity of the parts lying between the cerebral peduncles and the medulla oblongata. The gray matter of this division of the central nervous system also seems involved in the clonic movements, although these are only elicited in their full strength through action on the cerebral cortex (Kramer). Although these parts of the central nervous system are the most susceptible to the action of santonin, large quantities also affect the cord after division of the medulla oblongata and produce tonic con- vulsions resembling those seen in strychnine poisoning. The medullary centres seem to be comparatively little affected by santonin, the respiration being interfered with during the spasms, but returning to its ordinary rate and strength during the intervals. The 1 The view formerly held that the yellow vision was due to a yellow pigmentation of the vitreous humor or the retina is undoubtedly erroneous. 122 ORGANIC SUBSTANCES ACTING LOCALLY. circulation is altered only by the asphyxia, and the heart continues to beat long after the respiration has ceased. Santonin undergoes some oxidation in the tissues and is excreted in the faeces and urine in several forms, two of which have been exam- ined by Jaffe and found to be oxysantonins. The urine and some- times the faeces have a deep yellow color, which changes to red or purple when alkalies are added. A similar reaction is obtained from the urine after the administration of chrysophanic acid, as in rhubarb or senna, and a number of reactions are given to distinguish between these two pigments, which, however, it can scarcely be necessary to do frequently. Thus the red of chrysophanic acid is permanent, while that of the san- tonin pigment fades after a time, and reducing agents, such as zinc, remove the former, and not the latter, while barium and calcium precipitate the chrysophanic and not the santonin pigment. Santonin was formerly credited with some cholagogueand diuretic action, but more accurate investigations have shown that it has no such effects. According to Harnack and Hochheim, santonin lowers the temperature in most animals by increasing the loss of heat through dilation of the cuta- neous vessels ; it resembles in this respect several other convulsive poisons investigated by these authors. Santonin is universally used as a remedy for the round worm, As- caris lumbricoides, and most clinicians believe that it has a specific poi- sonous action on these animals, and that its undoubted effects are due to its killing them. In experiments on the entozoa outside the body, however, von Schroeder found that santonin solutions were by no means fatal to them, and he explains their therapeutic effects by sup- posing that santonin renders the intestine so unpleasant an abode for the parasites that they migrate from it voluntarily into the large bowel, and are carried out by the purgative. The worms are often found in active movement when passed after santonin, although this movement ceases very soon afterward from the exposure to cold. The alkaline salts of santoninic acid act in precisely the same way as santonin itself, but are less suitable as anthelmintics, owing to their greater solubility and rapid absorption. A number of santonin derivatives have been examined by Coppola, who found that many of them produced effects which were practically identical with those of santonin, while in others the stage of convulsions was preceded by one of depression. PREPARATIONS. Santonica (U. S. P.), Levant wormseed, the unexpanded flower-heads of Artemisia pauciflora. SANTONINUM (U. S. P., B. P.), C 15 H 18 O 3 , a neutral principle derived from Santonica. Santonin is colorless when freshly prepared, but assumes a yel- low color when exposed to the light. This does not seem to impair its activity materially, but it is preferable to avoid it by keeping santonin in amber-colored vials. Dose, 0.03-0.1 G. (-2 grs.). TROCHISCI SANTONINI, each containing 0.03G. (| gr.) of santonin, U. S.P.; each containing 1 gr., B. P. ANTHELMINTICS. 123 Therapeutic Uses. Santonin is used almost exclusively to remove Ascaris lumbricoides from the intestine. It is much less effective against tapeworm or other intestinal parasites. The lozenges are generally prescribed, one for children, two for adults, U. S. P., while the dose of the B. P. lozenge is one for an adult. Lewin recommends the admin- istration of santonin in oily solutions, especially in castor oil, as less is absorbed from the stomach than when it is prescribed in other ways. The bowel ought to be emptied by suitable diet and a laxative before the santonin is administered, and a sharp purge ought to be given 24 hours afterwards in order to bring away the entozoa. Santonin has been advised in some retinal diseases, but the results have generally been unsatisfactory. Poisoning. In cases of poisoning, the stomach and bowel ought to be evacuated as rapidly as possible by the use of emetics or of the stom- ach tube, and of purgatives cr enema. The convulsions may be con- trolled by the use of chloroform or ether. The xanthopsia requires no treatment, and is not to be regarded as heralding any dangerous develop- ments, as it occurs to some degree in the great majority of cases in which santonin is administered. BIBLIOGRAPHY. Binz. Arch. f. exp. Path. u. Pharm., vi., p. 300. Lewin. Berl. klin. Woch., 1883, p. 170. Luchsinger. Pfl tiger's Arch., xxxiv., p. 293. Jaffe. Ztschr. f. klin. Med., xvii. Suppl., p. 7. Ztsch. f. phys. Chem., xxii., p. 538. Falck. Deutsche Klinik, 1860, p. 257. Kramer. Ztschr. f. Heilkunde, xiv., p. 303. Turtschaninoiv. Arch. f. exp. Path. u. Pharm., xxxiv., p. 208. v. Schroeder. Ibid., xix., p. 290. Nayel. Ztschr. f. Psychol. u. Phys. d. Sinnesorgane, xxvii., p. 267. Harnack. Zts. f. klin. Med., x'xv., p. 16; Arch. f. exp. Path. u. Pharm., xlvi., pp. 272, 447. Rose. Virchow's Arch., xvi., p. 233; xviii., p. 15; xix., p. 522; xx., p. 245; xxviii., p. 30. Hufner. Arch. f. Ophthalmol., xiii., p. 309. Preyer. Pfluger's Arch., i., p. 299. Coppola. Maly's Jahresbericht, xvii., p. 92. Filehne. Pfl tiger's Arch., Ixxx., p. 96. SPIGELIA. Another remedy used in cases of round worm is pink root, Spigelia mari- tima (U. S. P.), the active principle of which is unknown, although an alkaloid, spigeline, is said to occur in it. Occasional cases of poisoning have been observed, especially in children, the symptoms consisting in flushing and dryness of the skin, often with some cedematous swelling of the face, delirium and sopor followed by dimness of sight or temporary blindness. In frogs spigelia appears to depress the brain and spinal cord, and the heart beats more slowly and weakly, while in rabbits the most prominent symp- toms arise from the breathing, which becomes slow and labored and finally ceases in a convulsive attack. In the dog and cat its injection is followed by vomiting, great weakness and incoordination of the movements, restless- ness, rapid dyspnoeic respiration and finally by stupor, coma and death from failure of the respiratory centre. Spigelia (U. S. P.), the rhizome and roots of Spigelia uiarilandica. 124 ORGANIC SUBSTANCES ACTING LOCALLY. Fluidextractum Spigelice (U. S. P.), 4-8 c.c. (1-2 fl. drs.). The fluidextract is used to remove round worms, which it seems to effect in very much the same way as santonin. It ought to be preceded and followed by a purge. One of the volatile oil series which is frequently used as an anthelmintic is that obtained from Chenopodium ambrosioides or American worm-seed. Oleum Chenopodii (U. S. P.), 0.2-0.3 c.c. (3-5 mins.). The oil is admin- istered on sugar or in an emulsion. PART II. ORGANIC SUBSTANCES CHARACTERIZED CHIEFLY BY THEIR ACTION AFTER ABSORPTION. I. NARCOTICS OF THE METHANE SERIES. ALCOHOL-CHLOROFORM GROUP. A LARGE number of the derivatives of the methane series are characterized by the production of depression of the central nervous system, more especially of the cerebrum, and some of them are per- haps the most extensively employed of all drugs. With the exception of alcohol, which has been known since prehistoric times, the use of the members of this series scarcely extends over more than half a century. From the large number of substances belonging to this division of organic chemistry which are possessed of narcotic powers, it would seem that the combination of carbon and hydrogen in the form characteristic of this series is possessed of a special relation to the protoplasm of the nerve cells, or in other words, carbon radicles combined in open chain form are possessed of specific depressant powers. As a general rule the greater the number of these radicles contained in the chain, the more powerful the action, provided the substance is not changed so as to become incapable of absorption. Thus, in the alcohol series a regularly ascending scale of toxicity is met, commencing with methyl and ethyl and passing through propyl, butyl and amyl alcohols, of which each succeeding member is more poisonous than its predecessor. The later members of the series, however, become less soluble in the body fluids, are less easily absorbed, and therefore less toxic. The toxicity of these bodies may also be reduced or removed completely by the presence of acid-forming groups. Thus ethyl alcohol (CH 3 CH 2 OH) is a powerful depressant, but propionic acid (CH 3 CH 2 COOH) is entirely inactive in this direction. Again, one hydroxyl group in a substance does not remove its narcotic action, while two hydroxyls reduce it very consider- ably or may destroy it entirely ; thus ethyl alcohol (CH 3 CH 2 OH) is prob- ably quite as active as ethane (CH 3 CH 3 ), but glycol (CH 2 OH CH 2 OH) is almost inactive. A still more striking example of the effects of several hydroxyl groups is seen in the comparison of propyl alcohol (CH 3 CH 2 CH 2 OH) with glycerin (CH 2 OH CHOH CH 2 OH), the former being a powerful depressant, while the latter is practically devoid of any such action on the central nervous system. Compounds of the fatty series may also lose their characteristic effects by their combination with more active radicles. Thus ethane (C 2 H 6 ) is a member of the narcotic series, but ethyl nitrite 125 126 ORGANIC DRUGS ACTING AFTER ABSORPTION. (C 2 H 5 O NO) cannot be classed with it, because the O NO group has a very powerful and entirely different effect ; very small quantities of ethyl nitrite are required to produce the nitrite effect, so that the depressant action is pushed into the background. Members of the methane series often lose their depressant action when combined with nitrogen so as to form substi- tuted ammonia. Thus trimethylamine (N(CH 3 ) 3 ) has no depressant action, although each of the methyl radicles alone would possess it. Again, the sub- stitution of a member of the aromatic series for one of the fatty substances sometimes changes the action from that characteristic of the alcohol-chloro- form group to that of the benzol series. For example, ether (C 2 H 5 O C 2 H.) is one of the most valuable anaesthetics, but if one ethyl radicle be substi- tuted by phenyl (C 6 H 5 O G 2 H 5 ), it loses this property entirely. Others, however, retain their depressant action, as, for example, acetophenone (C 6 H 5 -CO-CH 3 ). A very interesting hypothesis has recently been suggested by Meyer l and Overton 2 to explain why so many of the bodies of this series act as narcotics. Practically all of them are more soluble in lecithin and cholesterin than MI water and accordingly when they reach the blood they tend to accumulate in the nerve cells, which are rich in cholesterin and lecithin. Here they may be supposed to partially dissolve these constituents, or, at any rate, to change their relations to the rest of the nerve cells and this derangement of their normal condition leads to impairment of the function of these cells, or narcosis. But m-any other substances (e. g., many of the benzol derivatives) possess these physical properties equally with the members of the methane series, and yet induce no narcosis proper, so that though the physical characters of these drugs may probably be important factors in their action, they cannot be held to determine it solely. It is impossible to enumerate here all the substances of this series which possess more or less depressant action on the nerve centres. A very large number of them have been the subject of investigation, but only a few of them have become established remedies. Among the hydrocarbons the fifth, Pentane, and the eighth, Octane, have been proposed as anaesthetics for short operations, but have never received an extensive trial. Some of the unsaturated hydrocarbons have also been suggested, such as Amylene, which was introduced by Snow, but was found 1 to vary exceedingly in its properties, and proved to be a mixture of several isomers. One of these has lately been isolated and recommended for short operations under the name of Pental ( (CH 3 ) 2 = C CH CH 3 ). Another unsaturated hydrocarbon which has been shown to possess narcotic proper- ties is Acetylene, but its action on the heart is said to preclude its use in practical therapeutics. Among the alcohols, Ethyl alcohol (C 2 H.HO) stands preeminent from its extensive use in therapeutics as well as from its importance in dietetics and as a poison. Other alcohols have been found to resemble it in action, but the only one that has been introduced into therapeutics is Amylene hydrate, or tertiary isoamyl alcohol ( (CH 3 ) 2 C(OH)CH 2 CH 3 ), which has been recommended as a hypnotic. The ethers contain one very important member in Ethyl ether ( (C 2 H 5 ) 2 O), which is perhaps the best anaesthetic in use. 1 Arch. f. exp. Path. u. Pharm., xlii., p. 109, and xlvi., p. 338. 2 Studien u. d. Narkose. Jena, 1901. Gottlieb. Ergeb. d. Physiol., i., 2, p. 666. NARCOTICS OF THE METHANE SERIES. 127 The aldehydes possess narcotic properties, but ordinarily are irritant and of disagreeable odor, so that they have not been used in therapeutics. 1 Par- aldehyde (C 6 H 12 O 3 ), a polymer of ordinary aldehyde, is, however, one of the newer hypnotics. Several derivatives of the aldehydes have been in- troduced, such as Methylal (HCH(OCH 8 ) 2 ) and Acetal (CH 3 CH(OC 2 H.) 2 ). Another important aldehyde derivative is Sulphonal ( (CH 3 ) 2 C(SO 2 C 2 H 5 ) 2 ), which has received considerable attention of late years as a hypnotic. Two analogous compounds, Trional and Tetronal, in the first of which one, in the second both methyl groups are replaced by ethyl, are said to be more powerful than sulphonal. The only member of the ketones which has received attention at the hands of therapeutists, is Hypnone (C 6 H 5 COCH 3 ), which has been used as a hyp- notic. The esters, or ethereal salts, have been but little used as depressants, and seem to be much weaker in action than the corresponding ethers. 2 Some of them, as amyl nitrite, owe their use not to the action of the alkyl radicle, but to the acid with which it is compounded, and are therefore included in another group. One ester which has been used as a narcotic in therapeutics, and to a much greater extent in animal experiments, is Urethane, the ethyl ester of carbamic acid (CO(NH 2 )(OC 2 H 5 )). Analogous compounds recently recommended as hypnotics are Hedonal (CO(NH 2 )(OC 5 H n ) ), the carbamic ester of tertiary amyl alcohol, Veronal, or diethylmalonylurea ( (C 2 H.) 2 C(CONH) 2 CO), and Neuronal, or bromdiethylacetamide ( (C 2 H 3 ) 2 BrC-CONH 2 ). The acids of the methane series possess little narcotic action as a general rule, and have not been used in therapeutics for this purpose, though butyric acid is said to have distinctly depressant effects on the central nervous system. When hydrogen atoms of these acids are replaced by chlorine or bromine, they acquire a much stronger action ; thus acetic acid is practically devoid of narcotic action, while some of the chloracetic and bromacetic acids are narcotic. But their effects on the other organs of the body preclude their use in therapeutics. 3 Some of the most important members of this series are halogen substitution products, formed by replacing one or more atoms of hydrogen in the simpler substances of the fatty series by chlorine. This substitution often increases the narcotic power to a very great extent : methane (CH 4 ) is practically not depressant, but if one, two, or three of the hydrogen atoms in the molecule be substituted by chlorine, forming CH 3 C1, CH 2 C1 2 , and CHC1 3 , the narcotic power increases with each Cl added. The best known of these is Chloroform (CHC1 3 ), which is the most powerful anaesthetic in use. The analogous com- pounds, Ethylene Chloride (CH 2 C1 CH 2 C1) and Ethylidine Chloride (CH 3 CHC1 2 ), have fallen into disuse, but ethyl chloride (C 2 H 5 C1) has recently been recommended for short operations. Another important substitution product is Chloral, or chloral hydrate (CC1 3 CH(OH) 2 ), which is the hydrate of trichloral- dehyde (CC1 3 CHO). An analogous compound is Butyl chloral, or Croton chloral (C 3 H 4 C1 3 CH(OH ) 2 ). Chloretone or Aneson (trichlorpseudobutylalcohol, CC1 3 C(CH 3 ) 2 OH) and Isopral (trichlorisopropylalcohol, CC1 3 CHOHCH 3 ) have recently been recommended as hypnotics. Several compounds of chloral have been recently introduced into thera- peutics, such as Chloralamide (CC1 3 CHOH NHCHO), which is a combina- tion of chloral with formamide, and Chloralose (C 8 H U C1 3 O 6 ), a compound of chloral and grape sugar. It has already been mentioned that the substitution of chlorine for hydro- gen in the acids endows them with a narcotic effect. Another example of 1 Formaldehyde is used as a disinfectant. (See Formalin.) 2 Vogel, Pfliiger's Arch., Ixvii., p. 141. 3 Mayer, Arch. f. exp. Path. u. Pharm., xxi., pp. 97, 119. Pohl, ibid., xxiv. p. 142. 128 ORGANIC DRUGS ACTING AFTER ABSORPTION. the alteration of the properties of a substance by the substitution of chlorine for hydrogen is offered by glycerin, which in itself inert, becomes depressant to the central nervous system when its hydroxyl radicles are replaced by chlorine. 1 Some attempt has been made to introduce bromine instead of chlorine into the methane derivatives, because bromides are central nervous depressants, and it was hoped that a combination of the methane and the bromide effects could be thus obtained. But, as will be explained, the bromides owe their action to the bromide ion, which is not present in these organic compounds. Ethyl bromide (C 2 H 5 Br) has been used as an anesthetic, and Bromoform (CHBr 3 ) as a narcotic, but only to a limited extent. The analogous com- pounds formed with iodine possess a powerful action which is different from that of the other methane derivatives, and which precludes their use as nar- cotics. (See lodoform.) The augmented effect of these halogen substitution derivatives has been explained by reference to a supposed depressant effect of chlorine and bro- mine upon the brain. But even though this were proved to be the case, it would not elucidate the matter, for chlorine is not set at liberty in the tissues when chloroform is inhaled, the molecule acting as a whole. (See page 24.) The chlorine and bromine derivatives of methane are not only more power- ful drugs, but also more powerful poisons than the ordinary compounds : much less chloroform is required to anaesthetize than methane, but much less is required to kill. In addition, these compounds, especially those con- taining chlorine, seem to have a more powerful action on the heart and cir- culation and on the metabolism than the others. In other words, the chlo- rine bodies have a wider field of activity and are more nearly general protoplasm poisons. (See Chloroform.) All of the narcotics of the methane series resemble each other closely in their general action. This consists of a first stage of imperfect con- sciousness and confused ideas, followed by one of wild excitement, and eventually by complete unconsciousness, which may terminate in death. The second stage is much more marked after some of the series than after others, and is often entirely absent. It has given rise to the theory that these drugs stimulate the nerve cells before paralyzing them, but an alternative explanation is that the functions of control and inhibition are lessened, and the centres of motion are thus left free and act more strongly than normally. This question has been most discussed in regard to alcohol, and will receive greater attention under that heading. (See pages 133-135.) The depression of the central nervous system induced by these bodies is in the majority of cases accompanied by an alteration of the circulation of the brain in the direction of congestion or anaemia, and it was formerly believed that these drugs induced depression by caus- ing anaemia of the brain and thus starving the nerve cells. But this improbable explanation has been refuted by experiments in which all the blood of a frog was replaced by salt solution, and the brain cells thus deprived of nutrition before an anaesthetic was applied ; chloro- form then induced the same changes as in normal animals. There is no question at the present time that these bodies act directly on the ^Marshall and Heath, Jonrn. of Physiol., xxii., p. 38, and Kionka, Arch, internal, de Pharmacodyn., vii., p. 475, give a resume of the relation of the chlorine substi- tutes to the simple methane derivatives. ALCOHOL. 129 nerve cells, or rather on the central part of the neurons. Binz sug- gested that the change was of the nature of a coagulation of the protoplasm, but this theory is not supported by microscopic investiga- tion, and more recently histologists have been inclined to regard the ef- fects of the central nervous depressants as associated with alterations in the distribution of the chromatin in the nerve cells. A simple explanation of nervous depression has been suggested in the retraction of the dendrites. These finer processes of the nerve cells are supposed to serve to maintain the connection between the individual cells during consciousness by forming ramifications between them, while it is sug- gested that in natural sleep and in unconsciousness in general, the den- drites are withdrawn, and the cells are thus cut off from intercom- munication. Some changes which have been observed in the dendrites after narcotics might be explained in this way, but the explanation is only a hypothesis at present. There is, however, every probability that the nerve cell depressed by drugs undergoes changes similar to those of natural sleep and the changes in the brain circulation (anemia) may be regarded as the result and not as the cause of the depression in both conditions. While the members of this group resemble each other closely in their effects on the central nervous system, they are used for very different purposes in therapeutics and may therefore be discussed in three sub- groups : 1, alcohol ; 2, general anesthetics, and 3, narcotics or hyp- notics. It must be recognized, however, that there is no hard and fast line dividing these subgroups ; for the anaesthetics, chloroform and ether, may be used in small quantities to produce rest and sleep, and would then, strictly speaking, be narcotics ; while, on the other hand, chloral and sulphonal, which are generally used as hypnotics, give rise to complete anesthesia when administered in large quantities. I. Alcohol. Ethyl alcohol (CH 3 CH 2 OH) has been known in an impure form since the earliest times, and as far back as the history of medicine ex- tends, has been used as a drug. Its medicinal reputation has under- gone many fluctuations, by many held to be a panacea, by others it has been considered of little or no value as a remedy, but of the greatest importance as a poison. Alcoholic liquors are generally prepared by the fermentation of sugars, which either exist preformed in the fruits, or are derived from starch by a preliminary ferment action. The simple liquors (wines and beers) generally contain only a low percentage of alcohol (2-20 per cent.), and the stronger preparations (spirits) are prepared from them by distillation, which raises the percentage to 3060 per cent, and at the same time removes the non-volatile constituents. Spirits and liquors are not, however, simple mixtures of alcohol and water but contain many other volatile substances, the character of which is little known, and which are called oananthic ethers. Some of them have 9 130 ORGANIC DRUGS ACTING AFTER ABSORPTION. been shown to be higher members of the alcoholic series, while others would seem to be of entirely different constitution. The name is de- rived from their giving the odor and taste, or bouquet, to wines. Pure alcohol is obtained from these spirits by repeated distillation and by special measures designed to remove the w r ater. It is seldom used in medicine, some form of spirits, wine, or beer being prescribed instead. Action. The value of alcohol in medicine depends upon three chief points : 1, its irritant local action ; 2, its action on the central nervous system, and 3, its value as a food. The irritant action is not so marked as that of many other substances, but is of much greater importance, owing to the habitual use of this drug. It is probably due at any rate in part to the withdrawal of water from the cells and is shown by the results of its application to the skin, to wounds and to the mucous membranes. Applied to the skin in sufficient concentration (e. g., 6090 per cent.), it produces red- ness, itching and a feeling of heat like other volatile and irritant sub- stances, such as the volatile oils. Alcohol is, however, much less irritant and at the same time more volatile than these, so that unless its evaporation be prevented, it may produce a sensation of cold and have little or no irritant action ; this is especially the case when dilute alcohol is used, no very distinct appearances of irritation of the skin being produced by solutions under 4050 per cent. In ulcers and other unprotected surfaces, the irritant action is much greater and the cell division is accelerated, so that, judiciously applied, it may quicken the healing of such breaches of continuity. Concentrated solutions, however, cause a precipitation of the albumins, and act first as astrin- gents and later as corrosives, until they are diluted by the fluids of the wound. Its effects on mucous membranes are similar to those on wounds. In the mouth strong alcohol produces a burning, unpleasant sensation which passes to the throat and stomach when it is swallowed, and if the concentrated vapor be inhaled, it causes irritation and reflex closure of the glottis. The effects of alcohol on the digestive functions are so important that they will receive further attention (page 140), The action of alcohol on the Nervous Centres, differs a good deal in individuals. In small quantities it generally produces a feeling of well-being and good-fellowship, along with increased confidence in the powers, mental and physical, of the subject of the experiment. Larger quantities are followed by a certain amount of excitement, marked by laughter, loquacity and gesticulation. The face becomes flushed and hot, the eyes brighter and livelier, the pulse is accelerated. Even at this stage self-control is partially lost and the will power is weakened. The speech may be brilliant, but it often betrays the speaker ; the movements are more lively, but they are often undignified. The loss of self-control is often indicated further by furious outbursts of anger and unreasonableness, or by the indulgence in maudlin sentimentality and sensual fancies. The sense of responsibility and the power of ALCOHOL. 131 discrimination between the trivial and the important are lost, and the individual has no regard for the feelings of others or the ordi- nary conventions of life. If the boat be further continued, the movements become uncertain, the speech becomes difficult and stam- mering, the walk becomes a stagger, and a torpid slumber follows. Often nausea and vomiting set in, although these are entirely absent in some cases. On awaking from slumber, very great depression is generally suffered from, together with nausea and vomiting, and want of appetite, which may last for several days and is associated with all the symptoms of acute gastric catarrh. Very large quantities of alcohol lead to a deep, torpid sleep, which eventually passes into total unconsciousness, resembling the condition in chloroform anaesthesia ; the respiration becomes stertorous and slow, and the face, which has hitherto been flushed, becomes pale or cyanotic. This condition may last for several hours and end in death from failure of the respiration, but in other cases the anaesthesia be- comes less deep, and after a very prolonged sleep the patient recovers. When the stage of anaesthesia is reached, it lasts very much longer than that produced by chloroform and ether. It is said that persons rarely or never recover if unconsciousness lasts longer than 1012 hours after the drinking bout. The effects of alcohol vary greatly, however, in different individ- uals and in the same individual at different times. One person is rendered sentimental, another bellicose, while in a third there may be no appearance of excitement, the first distinct symptom being pro- found slumber. When drinking is indulged in in company, the excite- ment stage is a very common phenomenon, but if alcohol is taken without the exhilarating accompaniments of bright lights and exciting companionship, it is much less frequently seen, and the question has therefore arisen how far the environment produces the excitement in alcoholic intoxication. It may be stated at once that there exist two distinct views as to the action of alcohol on the central nervous system : the one stoutly upheld by Binz and his pupils, that alcohol first stimulates and then depresses the nerve cells ; the other championed by Schmiedeberg, Bunge and their followers, that it depresses the central nervous system from the beginning. The symptoms of excitement require no explanation on the first theory, which is rather to be looked on as the natural expres- sion of the facts observed. On the other hand, Schmiedeberg ex- plains them as not due to true stimulation of the motor areas, but as the result of these areas being freed from control by the weakening of the highest functions of the brain the will and self-restraint. Even the smallest quantities of alcohol tend to lessen the activity of the brain, the drug appearing to act most strongly, and therefore in the smallest quantities, on the most recently acquired faculties, to anni- hilate those qualities that have been built up through education and experience, the power of self-control and the sense of responsibility. The question is a most difficult one to decide, for on the one hand it 132 ORGANIC DRUGS ACTING AFTER ABSORPTION. has been shown that the simplest movement is the result of a combi- nation of motor and inhibitory impulses from the brain, while on the other hand the measurement of the relative strength of these impulses is one of the most difficult problems of biology. The advocates of the stimulant action point to the confidence in their own powers exhibited by intoxicated persons, to the brilliancy of the after-dinner speech, and to the excitement stage as evidences of the increased activity of the brain. But their opponents question whether the confidence is accom- panied by any really increased physical strength, and point out that the brilliancy of speech may be due to the environment and to the speaker having lost his habitual shyness and nervousness, and that the excitement is generally absent when the associations are different, or degenerates into a form which more distinctly resembles depression. More definite evidence for or against the stimulant action of alcohol has therefore been sought by comparing the amount of work which can be done with and without it; and an apparent confirmation of Bunge's view has been found in the results of the use of alcohol by troops on the march, for repeated experience has shown that those regi- ments which were not supplied with alcohol marched farther and were in better condition at the end of the day than others to which it had been given. Forms of work requiring larger drafts upon the intel- ligence than the marching of soldiers are also performed less correctly with alcohol than without it ; thus typesetters can do more work and make fewer errors when they abstain from its use. The capacity for work depends not so much upon the actual strength of the muscles as upon the condition of the brain, and these experiments are therefore generally quoted as evidence of the depressant action of alcohol. Their results are not incompatible with the view that alcohol primarily stimulates the nerve cells, however, for Binz and his followers allow that the stimulation is transient and is followed by depression, and if a sufficient time elapse after the alcohol is taken, the stage of depres- sion is elicited and the total work may thus be reduced. A more exact method of examining the initial effects of alcohol on work is afforded by measuring at different intervals after the drug is given the work of which a muscle is capable before it is completely fatigued. This has been done in a number of experiments with the ergograph and the dynamometer, which have not all given the same result ; the majority of the investigators hold, it is true, that the initial effect of small quantities is to increase the capacity for work, but this effect is a tran- sient one and is quickly followed by a marked loss of power (Hellsten) ; in fatigue the stimulating effect is much more evident than in untired muscles, and all observers are agreed that only the smallest quantities elicit this action. The interpretation of the observation is disputed, some regarding the initial increase of capacity as evidence of transient cerebral stimulation, others attributing it to the alcohol acting as a muscle food or affecting the peripheral nerves. The measurement of intellectual work is, of course, much more difficult, and the results are very liable to misinterpretation, but ALCOHOL. 133 Kraepelin found in a series of careful measurements of the simpler cerebral processes that the receptive and intellectual powers were weak- ened by very small quantities of alcohol, while the motor functions seemed to be facilitated by small, and retarded by large quantities. For example, a person under even a small dose of alcohol makes more errors than usual in adding a row of figures and in reading a series of unconnected syllables, and apparently recognizes letters and words somewhat more slowly. It is interesting to find that the subject of the experiment is quite unaware of the inferiority of his work and is often persuaded that it is unusually good. Kraepelin's latest investigations tend to show that this effect of alcohol lasts much longer than is gen- erally recognized, the mental equilibrium being reinstated only 12-24 hours after even very moderate indulgence in alcohol. He leans to the view that alcohol weakens and paralyzes some parts of the brain, while primarily stimulating others, but brings forward no new evidence that this stimulation is not fictitious and really due to the removal of the barriers of self-restraint by the paralysis of higher areas. Jacob] found that small differences in weight could be estimated more correctly under alcohol than in the normal condition of the brain, and this would seem at first sight to indicate primary stimulation, but he believes that the true explanation is a retardation of the cerebral processes. The sensation of pain is also found to be lessened by even small quantities of alcohol. No unequivocal evidence of the initial stimulant action on the brain has yet been adduced, for each new feature may be inter- preted as really due to the depression of controlling or inhibitory func- tions. Of course, there is no absolutely convincing proof that no stimulation of the motor areas occurs, and no physiological proof of the existence even of controlling areas can be adduced, much less of their paralysis by alcohol. Ou the other hand, no other known drug stimulates the motor areas only, without increasing the activity of the lower parts of the system at some stage of its action, and the advocates of the stimulant action have to consider chloroform and ether also brain stimulants, for they cause a stage of excitement very similar to that pro- duced by alcohol, and, in fact, have been used as habitual intoxicants. Acute alcoholic intoxication leads to very distinct alterations in the histo- logical appearance of the cells of the central nervous system, which have been described by Dehio, Stewart and others. The chief change noted by them consists in replacement of the chromatin network by fine granules, which in turn seem to become dissolved in the general cytoplasm. Staining reagents, therefore, give rise to a diffused coloration of the cell rather than to localized masses of color, such as are seen in the normal cell. The den- drites are shortened and exhibit rounded nodosites along their course. In the lower parts of the central nervous system the evidences of primary depression are less open to question. For example, the coor- dination of the movements suffers at an early stage in alcohol drink- ing, long before the generally recognized forms of lack of coordination, such as indistinct speech and staggering, appear. In the spinal cord alcohol causes a depression of the reflex irritability, which passes into complete paralysis some time before the respiration ceases. 134 ORGANIC DRUGS ACTING AFTER ABSORPTION. The medulla oblongata is the last part of the central nervous system to be acted on by alcohol, or at any rate to undergo complete pa- ralysis. The Respiratory and Circulatory Centres preserve their func- tions long after the occurrence of complete unconsciousness and the disappearance of the ordinary reflexes. The same question has been raised in regard to the respiratory centre, as has been already dis- cussed in the consideration of the brain, and the same two opposing views have been upheld. These are of greater importance as regards the respiratory centre, because the advocates of the stimulation theory advise the use of alcohol in conditions of the respiration in which it is directly contraindicated if the other view be the correct one. The question here is apparently much more simple, because the ac- tivity of the respiratory centre can be estimated directly by measuring the number of the respirations and the amount of air inhaled during each ; but a large number of such experiments .have been performed with very varying results. If the number of the respirations be counted in a person in the excitement stage of alcoholic intoxication, it is often found to be much greater than normally, but this may be due to the muscular movements and need not indicate any direct action of the drug on the medullary centre. And, of course, this excitement stage is not elicited in therapeutics, and the value of alcohol as a res- piratory stimulant must therefore be estimated in cases in which no such excitement is caused. A number of such estimations have been made in man and animals, and on the whole the evidence shows that in man even when no excitement is produced and in some instances even when sleep follows, the amount of air inhaled is larger than before the drug was administered (Jaksch, Zuntz and Berdez, Geppert, Weissenfeld, Wendelstadt) ; the increase is generally more evident when alcohol is taken during fatigue and exhaustion than in ordi- nary conditions. This may not indicate a direct stimulation of the respiratory centre, however, for the increase is often not greater than that following an ordinary meal, and may therefore be attrib- uted to the respiratory centre being indirectly affected by the activity of the stomach and intestine. And it is to be noted that alcohol may have more indirect effect on the respiration than ordinary food because it is so much more irritant to the stomach wall. These experiments failing to determine whether the respiratory centre is directly stimulated in man, another method has been employed by Loewy in which the excitability of the centre was estimated by its response to the stimulus of an increase of the carbonic acid in the blood. Unfortunately, his experiments were too few to permit of general inferences, but they lend no support to the theory that the irritability of the centre is increased. There is therefore no sufficient evidence that the respiratory centre is directly stimulated in man and the increase in the amount of air inhaled may be due to the peripheral action of alcohol. In the dog, no acceleration of the respiration occurs after alcohol, while in the rabbit, on the other hand, the respiration is much accelerated, and ALCOHOL. 135 the amount of air inhaled shows a corresponding increase. Jacquet has attempted to show that this is due to the local action of the alcohol, and not to any direct effect on the nervous sytem, but his results have been disputed by VVilmanns ; Singer also refuses to recognize the changes in the rabbit's respiration as an indication of direct action on the respiratory centre and is disposed to attribute them to the irritation of the stomach and the increased muscular activity which is rendered necessary by the loss of heat entailed by the dilatation of the cutaneous blood vessels. In short, there is no unequivocal evidence that the increase in the respi- ration under alcohol in health is due to direct stimulation of the respiratory centre, while on the other hand, no depression of the activity of this centre occurs except at a late stage of alcohol poisoning. Alcohol is often said to slow the respiration in fever patients and to stimulate it in cases of shock. In the first case, however, there need be no direct action on the respiratory centre, for it seems much more likely that the improvement (when present at all) is due to the alcohol lessening the excitement through its narcotic action. The pathology of shock is so little understood that it would be use- less to attempt to explain its therapeutics, but if, as is held by many, shock is a condition of great inhibitory activity, the action of alcohol may be explained by its depressant effects, while on the other hand, it is difficult to explain these two contradictory effects on the theory that alcohol is a stimulant. The whole question might be supposed to possess merely theoretical interest ; in cases in which the respiration is insufficient it would seem that it is of little moment whether it is improved by a direct increase in the activity of the centre, or by some peripheral action. This is not correct, however, for if the respiration is increased only to cope with the products of the augmented activity of the alimentary tract, the general economy may profit little. On the other hand, if the air inspired is augmented in a greater ratio than these products, as is the case when the centre is directly stimulated, the advantage to the organ- ism is correspondingly great. The action of alcohol on the Circulation is no less disputed than that on the respiration, and the same divergence exists in the statements of the supporters of the stimulation theory. The real foundation for this view is here again the acceleration of the pulse during the excitement of alcoholic intoxication, which may be due to the increased muscular effort and not to any direct action on the heart. Jacquet has shown that the pulse rate is unaltered by alcohol in normal cases, provided that no excitement be produced by the environment. In animals alcohol has no effect on the pulse rate, unless given in very large quan- tities, when it produces effects similar to those described under chloro- form and ether weakening of the auricular systole, and later of the ventricular, with distention of both cavities and slowing. The effects of alcohol on the heart are, however, very much less marked than those of chloroform, for Dieballa found that 48 times as much alcohol as chloroform was required to modify the movements of the frog's heart, and that in order to bring it to a standstill 192 times as much alcohol was required. Loeb has recently shown that the cat's heart continues to beat strongly when a 2 per cent, solution of alcohol is perfused through the coronary vessels. Alcohol having been shown 136 ORGANIC DRUGS ACTING AFTER ABSORPTION. FIG. 2. Tracing of the dog's ventricle under alcohol. 8 c.c. (2 drs. ) of 50 per cent, alcohol were injected into a vein during this tracing, but no effect whatever is visible in the movement of the heart. Du ring- systole the lever moves upwards, during diastole downwards. (The tracing is to be followed from left to right.) FIG. 3. Tracing of the movements of the ventricle (lower) and auricle (upper) of the dog when a large dose (20 c.c. or % oz. ) of 50 per ceut. alcohol is suddenly thrown into a vein. The levers move upwards during systole, downwards during diastole. A, normal. B t injection. The systole of the auricle is very much weakened, the diastole is less affected. The ventricular systole is comparatively little changed, although it also is a little weaker. The effect passes off very rapidly, so that at the end of the tracing both chambers have almost recovered. A very similar effect is seen under chloroform. (Fig. 9.) (The tracing is to be followed from right to left.) ALCOHOL. 137 not to increase the rate of the heart, its advocates have begun to state that the force of the contraction is augmented, without, however, bringing forward any evidence of this worthy of attention. In animal experi- ments it has been shown that the first effect of alcohol on the heart is lessened efficiency and weakness of the contractions. (Figs. 2 and 3.) The flushing of the skin which occurs in alcoholic intoxication would seem to point to some vascular action, but it is impossible to say at present what the nature of this action is. It indicates dilation of the skin vessels, but whether this is of central or peripheral origin, whether due to stimulation of dilator centres or paresis of vaso-constrictors, is unknown. The widening of the blood path through this dilation is but slight, and produces little or no fall in the general blood-pressure. Very large quantities of alcohol cause a marked fall in the arterial tension, through weakening the vaso-constrictor centres and the heart muscle, but the quantities of alcohol required to cause any great fall in blood-pressure are far in excess of those used in therapeutics. It has been suggested that the widening of the arteries may in itself relieve the heart by lessening the resistance against which it has to con- tract, but it has yet to be proved that any marked dilation of the vessels occurs before the direct action on the heart muscle. Some evidence of this is forthcoming, it is true, for Hammeter found the velocity of the blood current increased by alcohol, but he does not state the quantity used in his experiments. The slowing of the heart which often follows the administration of alcohol in fever, would seem due rather to its diminishing the cerebral excitement than to its direct action on the heart. On the other hand, the alleged improvement of the circulation in shock may be due to a reflex from the irritant local action, and certainly would not seem to require any direct cardiac action for its explanation. Alcohol has little effect on Muscle or on peripheral Nerves when it is carried to them by the blood, but Lee states that frog's muscle is stimulated by small quantities and weakened by larger amounts. When a frog's nerve is exposed to alcoholic vapor its irritability is first increased and later diminished if the quantity applied be large enough. This fact has been used by Scheffer to explain the results of ergographic experiments in which the amount of work done under alcohol is at first augmented. He regards this augmentation as due not to central stimulation, but to the peripheral processes being facilitated. The sensory fibres are said to be depressed before the motor. The eifect of alcohol on the Digestion has been the subject of many in- vestigations, both from the clinical and the experimental point of view. There exists a widespread belief in both lay and medical circles that small quantities of alcohol taken before a meal increase the appetite, while after food they accelerate the digestion. It is obvious that alcohol may aifect digestion either by altering the activity of the fer- ments in the digestive canal, or by altering the secretion, movement, or absorption of the stomach and intestine. The digestive power of the ferments outside the body has been found to be unaltered or slightly increased when alcohol is present in very small quantity. In 138 ORGANIC DRUGS ACTING AFTER ABSORPTION. a solution of 510 per cent, of alcohol or of spirits, however, the gas- tric juice digests very much more slowly than normally, and the pan- creatic secretion is affected prejudicially by even smaller quantities. (Chittenden and Mendel.) Very large quantities of alcohol precipitate the proteids, but it. is unlikely that sufficient alcohol to produce this effect ever remains in the stomach for any length of time. The malt liquors and wines are much more detrimental to the digestive ferments than pure alcohol or spirits, and the augmentation of the activity of the ferments is so slight in any case that it does not seem likely that it plays any important role in the effects of alcohol on the stomach. The presence of alcohol in the mouth causes (according to Chitten- den, Mendel and Jackson) a very appreciable increase in the secretion of the saliva, presumably by reflex action. As regards the action on the stomach wall, it is to be remembered that alcohol, even in compar- atively dilute solution, is an irritant, and therefore leads to increased activity of the cells, a more active circulation in the organ, and prob- ably to a more rapid secretion of both acid and solids of the gastric juice. But apart from this local action on the stomach, it appears to exert a specific action on the secretion after its absorption into the cir- culation. For when it is injected into the dog's rectum, a profuse secretion from the gastric mucous membrane follows, and when part of the stomach is isolated from the rest of the organ, so that alcohol given by the mouth fails to enter it, this part still shares in the secretion. According to Radzikowski, the pepsin secretion is not always cor- respondingly augmented, the alcohol not accelerating the formation of pepsin from propepsin but merely leading to the secretion of the pepsin preformed in the cells. Similar effects have been obtained in man by Spiro, who administered alcohol by the rectum. It has been further demonstrated that the absorption of fluids from the stomach and bowel is much accelerated by the addition of alcohol (Brandl, Scanzoni, Farn- steiner, Tappeiner), and the movements of the stomach are also aug- mented by moderate quantities. (Klemperer, Batelli.) Digestion in the stomach may thus be influenced in two opposite di- rections when alcohol is administered in the usual form of wine, spirits, or beer. The action on the ferments is deleterious while the changes in the stomach wall, the increased secretion and movement and the accelerated absorption, are beneficial in many cases. These two opposing factors may neutralize each other, as in the dog in which the rate of diges- tion is scarcely altered, the retarding effects of alcohol on the proteolysis being compensated for by the more abundant secretion of the juice, which continues after the alcohol is absorbed, and therefore after its deleterious effects on the fermentation have disappeared. (Chittenden, Mendel and Jackson.) In man the result varies, the one factor pre- dominating in some cases, the other in others. Thus, while Kretschy and Buchner found that the digestion of proteids in the human stomach was distinctly retarded by alcohol and beer, Eichenberg, Wolffhardt and others state that small quantities of alcohol or wine accelerate the ALCOHOL. 139 digestion, and Gluzinsky came to the conclusion that as long as alcohol remains in the stomach the digestion is retarded, but that after its ab- sorption the digestion progresses more rapidly than if no alcohol had been given. Zuntz and Magnus-Levy have shown that the addition of beer to the dietary does not affect the absorption and utilization of the food by the tissues. It is not unlikely that the taste has some influ- ence on the result, that in those who enjoy the taste of alcohol, it in- duces a more rapid secretion and an improved digestion, while in those to whom it is disagreeable, the secretion is less altered. The divergence of opinion exists only in regard to the effects of small quantities, for all are agreed as to the deleterious action of any but moderate doses of alcohol on the digestion. After large quantities the irritation of the stomach wall is so great that nausea and vomiting are induced. There is every reason to suppose that this is due to the local irritation, and not to the action of the absorbed alcohol on the nervous centres. A large dose of concentrated alcohol sometimes leaves evidence of its irritant action in redness and injection of the mucous membrane and, it is said, in ecchymoses, but in most cases of fatal poisoning no such appearances are to be observed after death. Is Alcohol a Food ? This has long been discussed, and that with more passion and prejudice than are generally elicited by pharmacolog- ical questions. It was formerly supposed that the alcohol absorbed from the stomach was excreted unchanged by the lungs, skin and kidneys, and therefore gave up no energy to the body in its passage through it. But it has been shown that only the small amount of from 510 per cent. 1 of the ingested alcohol is really excreted in this way, and that mainly by the kidneys and lungs, the skin taking prac- tically no part in the excretion. The rest of the alcohol absorbed from the stomach and bowel, amounting to over 90 per cent., undergoes combustion. The fact that none of the products of the combustion have been isolated from the body does not invalidate this statement, for the corresponding products of sugar are not known, but there is no doubt that sugar is oxidized in the body. 2 According to Grehant's recent work, the oxidation of alcohol progresses slowly, appreciable amounts being found in the blood twenty -four hours after its ingestion ; this accords with Kraepelin's statement that its effect on the brain can be 1 Kecent investigations suggest that even this is too high a valuation tor the alcohol excreted and that only 2-3 per cent, of that ingested escapes oxidation. In particular there seems reason to question whether anything more than traces escape by the lungs. A very small quantity appears in combination with glycuronic acid in the urine of some animals, notably the rabbit. 2 It has been suggested that the oxidation of alcohol in the body may not give rise to the same products as its oxidation in the chemical laboratory. If aldehyde were formed it would be excreted in part by the lungs and kidneys, for aldehyde injected into the blood at once appears in the breath and urine. Acetic acid has never been identified with certainty after alcohol, but formic acid is excreted after methyl alcohol, and it therefore seems probable that ethyl alcohol is oxidized to acetic acid immediately, and that this at once undergoes further decomposition. 140 ORGANIC DRUGS ACTING AFTER ABSORPTION. detected for 12-24 hours. In undergoing combustion alcohol gives up energy to the body, and therefore is technically a food. This statement has met with a great deal of opposition, and the mere fact that alcohol gives up energy to the body does not constitute it an advisable food in all conditions. For example, the question might be raised whether alcohol does not require an amount of energy for its absorption equal to that liberated by its combustion, or whether its action on the nervous centres does not produce a greater waste of force than the food itself supplies. Both of these have been answered by experiments in which the carbonic acid excretion of the body has been measured before and after alcohol. Zuntz and Berdez and Geppert have shown by this method that after alcohol is taken, a slight rise of 510 per cent, occurs in the output of carbonic acid ; that is, a small amount of extra com- bustion goes on, a certain amount of energy is required for the absorp- tion, but this is not greater than that required for the absorption of any other form of food. And the total amount of carbonic acid ex- creted in 24 hours is not appreciably altered by alcohol, so that alcohol taken in addition to the ordinary food is either itself transformed into tissue, or undergoes oxidation instead of some substance which in turn is used to build up the body. Strassmann has shown that animals that receive alcohol tend to lay on more fat than others receiving the same food without alcohol, and this is in accord with the common observa- tion of the obesity of alcohol drinkers. Alcohol, therefore, acts as a substitute for fats and carbohydrates in the food to some extent. It has long been recognized that when insufficient fat and carbohy- drate is supplied to the body, the proteids are drawn upon to make good the deficiency and the nitrogen eliminated rises accordingly. On the other hand, when the fats and carbohydrates of the food are in- creased, the organism economizes its proteid and the nitrogen tends to fall. This is the most accurate method of testing the food value of non-nitrogenous substances, and alcohol has been the subject of a num- ber of such investigations. The divergent results have given rise in the last few years to a series of experiments which promise to become classical for the extraordinary patience and conscientiousness exhibited by those engaged in them as well as for the complete agreement in the results obtained by investigators who approached the subject with opinions which were diametrically opposed. These experiments, which may be cited as models of investigations in metabolism, were performed by Neumann, Atwater and Benedict, and Rosemann and his pupils. The results may best be illustrated by an account of Neumann's first experiment. This lasted 35 days divided into six periods. The proteids of the food and the carbohydrates remained constant throughout while alcohol was substituted for part of the fat for some time (see Fig. 4). Dur- ing the first five days, the nitrogen excreted was practically equal to that of the food (nitrogenous equilibrium), while during the next four days one half of the fat of the food was omitted and the immediate result ALCOHOL. 141 was an increase in the nitrogen excreted, indicating that the proteids of the body were being drawn upon to make good the deficit in the fat of FIG. 4. DAYS PERIODS FAT OF FOOD ALCOHOL NITROGEN 1 > sk .i i; - 8 9 Id 11 12 ir: n|lo 16 17 IS 19 20 a 2223 _>i '.-, v i ;';; I ^ 0. I ' i 56 o DA 11 ' / 3 . 1 % , y \ ,.. >,_ 7.3 OA i i / / ^~ \ "_ , ^ c \ IA LY \ ' ' \ / ^ ^ \ \ \ **^ \ / \ 7 X \ V ^ . - / The effect of alcohol on nitrogen elimination. The wave-line represents the nitrogen excreted. It rises rapidly in the second period when the fat of the food was reduced to one half, but soon falls in the third period where alcohol was substituted. 100 g. of alcohol is chemically equivalent to 78 g. of fat. (After NEUMANN. ) the food. The next ten days a quantity of alcohol chemically equivalent to the fat deficit was taken and the nitrogen elimination slowly fell to the normal (equilibrium). In the first five days of this period, however, the nitrogen remained high, showing that alcohol did not at first replace the fats completely. In the fourth period of six days, the same amount of fat was given as at first, while the alcohol was continued, and the nitrogen fell much below the amount ingested ; L e., the alcohol again led to a saving of the proteids. Next, both alcohol and fat were omitted for four days and the proteid tissues were again drawn upon. Finally the original diet was resumed and the nitrogenous equilibrium was at once restored. From this experiment Neumann drew the conclusion that alcohol can replace a chemically equivalent amount of fat in the dietary, for otherwise the nitrogen would not have returned to the normal toward the end of the third period ; and alcohol given along with a sufficient dietary leads to a further economy of the proteids just as additional fat would ; otherwise the nitrogen would not have fallen below the point of equilibrium in the fourth period. Certain objections which were made to this experiment by Rosemann have been refuted by his own work and by Neumann's, so that both investigators are now in accord. The final result of all these investigations is that alcohol can take the place of some of the fat in the food, and leads to the same economy of proteid as the ordinary non-nitrogenous constituents of the dietary. The first three or four days during which alcohol is substituted for fat it has little or no tendency to economize the proteids, but this is true of other forms of food also ; any sudden change in the non-nitrogenous 142 ORGANIC DRUGS ACTING AFTER ABSORPTION. food leading to a temporary increase in the nitrogen excreted, which persists until the tissues have become accustomed to the new dietary. Metabolism. It was formerly supposed that alcohol economized the body tissues in some ill-defined way, by means of a direct action on the protoplasm of the cells ; as it was expressed, alcohol lessened the combustion of the tissues. There is no reason to suppose that alcohol in ordinary quantities has any action on the tissues save as a food, for, as has been mentioned, the oxidation of the tissues as measured by the oxygen absorbed and the carbonic acid exhaled is only affected as it is by any other food. When very large quantities of alcohol are taken, and depression and sleep follow, the combustion of the body is reduced, not through any action on the protoplasm generally, but through the muscular movements being lessened. In the same way, during the ex- citement stage, the carbonic acid exhaled is doubtless much increased, because more energy and -more of the body tissues is used up in the violent movements. Of course, the oxidation of alcohol by the tissues saves fat from combustion, and it is possible that some bodies which would normally be oxidized in the organism may pass through it un- changed in the same way ; thus it is stated that less benzol is oxidized in animals under the influence of alcohol than in unpoisoned ones. The influence of alcohol on the uric acid excretion seems to vary with the individual, for while no definite change has been observed in some cases, even when large quantities of alcohol were taken, Beebe found a distinct increase in the quantity excreted under moderate doses. He ascribes this result to alcohol disturbing the functions of the liver, and further evidence of this action has been found by Paton and Eason in the lower proportion of urea to the total nitrogen of the urine. The Temperature of the body falls somewhat after the administration of alcohol, but this is not due to any diminution in the oxidation and in the heat formed, but to the greater output of heat from the dilation of the skin vessels. The fall in temperature is comparatively slight, seldom being more than J-l C., but it would seem that exposure to cold causes a greater fall in the temperature after alcohol than in nor- mal conditions ; this is perhaps due to the temperature-regulating mechanism being rendered less sensitive by alcohol. The fall in temperature produced by alcohol is generally accompa- nied by a feeling of heat, and a thermometer applied to the skin may actually show a rise of several degrees, because more warm blood flows through the dilated vessels. If much excitement and movement follow the ingestion of alcohol, no fall in the temperature may result, the in- creased heat formed during the movement compensating for the increased output, and in some cases a rise of temperature occurs from the same cause. Very large quantities of alcohol may lead to a fall in temper- ature of 3-5 C., owing to the lessened movements during uncon- sciousness. The alcohol which escapes combustion in the tissues is excreted by the kidneys and perhaps by the lungs. Traces are sometimes found ALCOHOL. 143 in the sweat and milk, but there is no foundation for the legend that children may be intoxicated, or acquire a taste for strong drink from the alcohol absorbed in the milk of a drunken mother or wet-nurse. The amount and quality of the milk are unaffected by the adminis- tration of alcohol (Rosemann). Brauer states that alcohol is elimi- nated in some quantity in the bile and is then reabsorbed in the intes- tine. This is more marked in the case of amyl alcohol than in that of ethyl alcohol, and the appearance of alcohol in the bile is accom- panied by albumin, epithelial, cells and casts of the finer bile ducts. Although alcohol seems to increase the urine to some extent, it can- not be said to be a powerful diuretic in itself, and it is quite unknown whether it acts on the kidney directly or not. Some of the spirituous liquors such as gin, produce a profuse secretion of urine, but this is due to their other constituents, and not to the alcohol. Alcohol is generally credited with aphrodisiac powers, that is, with increasing sexual desire, although no less an authority than Shake- speare states that it prevents the consummation of sexual intercourse. The unquestionable tendency toward sexual excess observed in intoxi- cation is due, not to any effects on the generative organs, but to the loss of self-control from the cerebral action of the poison. Alcohol possesses only a weak antiseptic action, for while the growth of some bacteria is delayed somewhat in a 1 : 1000 solution, many grow abundantly in 4 per cent, alcohol, and some in even stronger solutions. Its disinfectant action has been the subject of a number of researches recently and has been found to vary with the conditions. Dry bacteria may be exposed to absolute alcohol for twenty-four hours without losing their vitality, while 60-70 per cent, alcohol is fatal to them, and also to moist organisms. The explana- tion of this curious observation seems to be that alcohol fails to pene- trate microbes unless in the presence of water. In less than 40 per cent, the action is very slow, so that the limits of alcohol as a disin- fectant may be placed at 5070 per cent. ; in this strength it is equivalent to about 3 per cent, carbolic acid, provided that it does not cause large precipitates of proteid. Many bodies which are antiseptic when dissolved in water have comparatively little effect when dis- solved in alcohol. (Compare p. 48.) It has long been recognized clinically that persons addicted to the use of alcohol show less resistance in acute disease and in operations accom- panied by shock than more temperate individuals, and in very intem- perate cases, the prognosis must be guarded in an attack which would ordinarily be accompanied with little danger. This has been confirmed by a number of experiments on animals which were subjected to treat- ment with alcohol and then inoculated with pathogenic germs (Laitinen). The results have invariably shown a greater susceptibility to infection and a greater mortality than in control animals which had received no alcohol. A similar effect was observed when toxines were injected instead of bacteria, and great difficulty was encountered in 144 ORGANIC DRUGS ACTING AFTER ABSORPTION. rendering animals immune to the diphtheria toxin if they had pre- viously been treated with alcohol. Various explanations of this reduced resistance have been given, Rubin ascribing it to paucity or inactivity of the leucocytes, while Abbott and Bergey found a reduc- tion in the hemolytic complement, which suggests that the suscepti- bility to infection may be due to the failure to form the specific com- plement to the bacterial toxin. It is often stated that alcohol given in the treatment of infectious diseases must have a similar deleterious effect on the resistance of the tissues, but this has not been shown to be the case, and some observers (Hare, Friedberger) indicate that it favors the defence of the organism. Repeated doses of alcohol produce tolerance, which, although not so great as that acquired for morphine and nicotine, involves the pre- scription of double or triple doses, in persons addicted to drinking. The close relationship between the narcotics of the fatty series is indicated by the fact that much more chloroform or ether than usual is required to anaesthetize persons in whom a tolerance for alcohol has been established. Methyl alcohol, or wood alcohol, has assumed great importance lately from a large number of cases of poisoning having occurred from its being substituted for ethyl alcohol as an intoxicant, or in some patent remedies. In animal experiments it is found that given in single doses it is slightly less poisonous than ethyl alcohol, the action coming on somewhat more slowly, but lasting a longer time; the symptoms of gastric irritation are generally more marked than those induced by ethyl alcohol, and very often some convulsive movements are observed (Hunt). When the administration is repeated, methyl alcohol is found much more poisonous than ethyl, and this may probably be ascribed to the more prolonged action of the former. Pohl has pointed out that while ethyl alcohol undergoes complete combustion in the tissues, methyl alcohol is oxidized to formic acid and possibly formic aldehyde, both of which are much more poisonous than the original alcohol. It seems a fair inference that the pro- longed action and the consequent greater toxicity of the lower alcohol may be due to these products. In man the symptoms of wood alcohol poisoning differ from those of ordinary spirits in the marked muscular weakness and defective cardiac action, which are followed by nausea, vomiting, coma, or delirium of a much more intense and persistent character than those seen in intoxication with ethyl alcohol. In a considerable number of cases death has followed from a single dose smaller than would have been fatal had ethyl alcohol been swallowed, and in some cases total and permanent blindness has followed or accompanied recovery. This condi- tion is more often the result of repeated ingestion of the alcohol, however, and is due to optic neuritis and subsequent complete optic atrophy. The large number of cases of blindness or fatal intoxication collected by Buller and Wood demonstrate clearly the danger incurred in the use of this poison inter- nally or even externally. Optic atrophy has been induced in animals repeat- edly by the administration of wood alcohol, and is certainly much less liable to occur from ethyl alcohol. The other alcohols are mainly of interest as impurities of the preparations of ethyl alcohol. They all resemble it in their general effects, but differ from it in toxicity; propyl alcohol is more powerful than ethyl, butyl than propyl, and amyl than any of them. Amyl alcohol, or fusel oil, is present in small quantity in most forms of spirits, especially when these are freshly distilled or ' ' raw. ' ' It resembles ethylic alcohol in general, but is more irritant locally, ALCOHOL. 145 and is believed by some authorities to have more deleterious effects in chronic poisoning than pure ethylic alcohol. This is not based on any very satisfactory evidence, however, and all the characteristic symptoms of chronic alcoholism have been produced in animals by pure ethyl alcohol. Furfurol is also present in many forms of spirits, but in such small quantities that it does not play any role in the symptoms induced by them. PREPARATIONS. Alcohol (U. S. P.) contains 92$ of alcohol (C 2 H.HO) by weight. Alcohol Absolut um (U. S. P., B. P.), absolute alcohol, contains not more than 1 % > by weight, of water. Alcohol Dilutum (U. S. P.) contains about 41$, by weight, of alcohol. Spiritus Rectificatus (B. P.), rectified spirit, contains 90 parts of pure alco- hol, by volume, and 10 parts of water (85.65$, by weight, of alcohol). There are four official dilutions in the B. P., containing 70, 60, 45 and 20 per cent, of alcohol by volume respectively. SPIRITUS FRUMENTI (\J. S. P.), whiskey, contains 44-50$ of alcohol by weight, and is obtained by distillation of an extract of fermented grain. SPIRITUS VINI GALLICI (U. S. P., B. P.), brandy, contains 39-47$ of alco- hol by weight, and is obtained by the distillation of fermented grape juice. Mistura Spiritus Vini Gallici (B. P.), a mixture of brandy, cinnamon water, sugar and yolk of egg (about 17 per cent, alcohol). Dose, 1-2 fl. oz. Non-pharmacopceial spirits, which are used occasionally in medicine, are gin and rum. These Spirits all contain, roughly speaking, about one half as much alco- hol as the three concentrated alcohols of the U. S. P. or the rectified spirits of the B. P. They contain, in addition to the ethyl alcohol proper, numbers of other volatile substances, some of which are alcohols of the same series as ordinary alcohols (butylic, amylic, etc.), while others are of entirely unknown constitution the cenanthic ethers. Brandy and whiskey act very much in the same way as pure alcohol, but are more powerful than would be expected from the percentage of alcohol alone. When freshly distilled they are much more irritant than when kept for some years. Numerous other preparations containing large quantities of alcohol, such as the spirits of the volatile oils, might also be included in this group, but they are not used, as a general rule, for the same purposes as the alcoholic preparations proper, and their effects are in part due to the volatile oils contained. Some of them have, however, been employed as intoxicants instead of brandy or whiskey, and Eau de Cologne and other essences have gained a certain notoriety as a means of secret drinking among women. The liqueurs are too numerous to mention, and their composition is extremely diverse. Many of them contain considerable quantities of sugar, and the combination of alcohol and sugar would seem peculiarly deleterious to the gastric mucous membrane. Others, such as cherry water (Kirschwasser), contain hydrocy- anic acid, and the others various bodies of the volatile oil series. None of them seem to have any properties which would recommend their use in therapeutics. The Wines and Beers are much weaker preparations of alcohol. The U. S. P. recognizes two forms of wine, YINUM ALBUM (white wine) and VINUM RUBRUM (red wine, claret). These both contain 7-12$ of alcohol by weight, along with 1.5-3$ of solid matter in the white wine and 1.6- 3.5$ in the red. The YINUM XERICUM (sherry) of the B. P. contains not less than 16$ of alcohol by volume, while the VINUM AURANTII (B. P.), or orange wine, contains 10-12$ by volume. In addition, the wines contain the same volatile constituents as brandy, although in smaller amounts. Other wines are prescribed in medicine, some of which, such as port 10 146 ORGANIC DRUGS ACTING AFTER ABSORPTION. (15-20^), contain larger, and others smaller quantities of alcohol (hock and champagne 8-13%). The red wines contain a form of tannic acid derived from the skin of the grapes, and both red and white often contain consider- able quantities of acids, chiefly tartaric acid. The amount of sugar varies with the different wines, and in fact in wine from the same locality but of different seasons. These constituents may lend to the wines a local dele- terious action on the stomach, more especially when they are taken habitu- ally. Champagne and the other sparkling wines contain large quantities of carbonic acid, which acts as a stimulant to the gastric mucous membranes. Champagne is considered one of the most l ' stimulant ' ' of alcoholic prepa- rations, although it contains a very low percentage of alcohol compared with spirits, a fact which is of some significance in the explanation of the "stim- ulant" effects of alcohol. The beers are not pharmacopceial, and are less frequently advised than the other preparations. They generally contain a comparatively small per- centage of alcohol (4-10%), along with a large amount of solids. These solids consist mainly of dextrin, sugar and other starch products, which retard the absorption of the fluid, but are of considerable value as foods. The hops added in the preparation have probably no action save as bitter stomachics. The alcohol of beer is comparatively slowly absorbed owing to the colloid constituents, and this allows time for fermentation changes in the sugars and dextrins, which may perhaps account for the discomfort produced by malt liquors in persons of feeble digestion. When beers and porter do not de- range the digestion, they are the most nutritive of all the alcoholic prep- arations, owing to the large amount of carbohydrates they contain. Therapeutic Uses. Alcohol is used externally in very dilute solution as a cooling application to the skin, and in threatening bedsores, in which it is often applied as brandy, whiskey, or dilute alcohol in order to harden the epidermis. It has been employed as an antiseptic and mild irritant to broken surfaces, and if applied to the skin in concen- trated form, and especially if kept from evaporation, acts as a rubefa- cient and irritant. In the form of diluted claret it is not infrequently used as an astringent gargle. The indications for the internal use of alcohol are ill defined, and cases which one physician would treat with alcohol, often seem to pro- gress as favorably without it in the hands of another. It is not suffi- ciently recognized that this drug possesses several different qualities, as local irritant, narcotic and food and that while one property considered alone might render it unadvisable in a given condition, the deleterious effect induced in this direction may be more than counterbalanced by its valuable results in other directions. At the same time it would be preferable in most cases to substitute for this conjunction of good and bad properties other drugs with a less extended sphere of action. One series of symptoms which is often treated with wines is of gas- tric origin, and is manifested in want of appetite and enfeeblement of the digestion ; in some of these cases the alcoholic preparations seem to be beneficial, while in others they appear to be positively harmful. This may be explained by the effect of alcohol on secretion and absorption, only those cases in which secretion is deficient being benefited, but the tastes of the patient are also an important factor ; if he enjoys the taste and odor of wine, its administration may promote his appetite, while, ALCOHOL. 147 on the other hand, if he has a distaste for wine, it will prove harmful. There is no question that the functions of the stomach are increased by pleasing, and retarded by unpleasant tastes and odors. In these cases "dry" wines are to be preferred, as the sugar of the sweet wines may irritate the stomach ; champagne may be used, and the wine ought to be given immediately before or during a meal. Cases of hemorrhage, shock, and other forms of severe and sudden depression of the heart and central nervous system are very frequently treated by the administration of strong alcoholic preparations, such as brandy and whiskey, this treatment being based upon the belief that alcohol is a cardiac and respiratory stimulant, the grounds for which have already been examined. It is extremely difficult to estimate the value of a remedy in these conditions, and it is possible that the irri- tant action of alcohol in the stomach may increase the activity of the medullary centres refiexly, or that by its narcotic action it may lessen the anxiety and pain of the patient. On the other hand, in cases of inhibitory slowing of the heart it may aid by lessening the activity of the vagus centre in the medulla. But the beneficial effects of alcohol in these cases has been much questioned in recent years and the belief that it is of little value is certainly more widely held at present than at any previous time; in experimental shock in animals, Crile found that alcohol generally increased the danger when given in average doses, and that smaller doses had no beneficial effects, but it is quite possible that in man different results may be obtained from alcohol acting as a narcotic and removing nervous symptoms which would not arise in the lower animals. In sudden chill with a tendency to fever, alcohol is often of great benefit, especially when taken in the form of brandy or whiskey diluted with hot water. Its efficacy here would seem due to the relief of the congestion of the internal organs by the return of the blood to the skin. In many cases of acute inflammatory disease, the prescription of alco- hol seems to be attended with benefit, while in others it seems rather to increase the severity of the symptoms. No special indications can be given for alcohol in these cases, and the physician must be guided by its effects. An old rule advised that if the pulse becomes slower, the temperature falls, the respiration is deeper, the nervous symptoms are ameliorated and the skin becomes moister after the administration of alcohol, the treatment ought to be continued ; but this is merely equivalent to advising the continued administration of alcohol when it is found to improve the symptoms. The effect of alcohol in these cases is often said to be a stimulant one on the heart and central nerv- ous system, but it would rather seem to allay the irritability of the nervous centres, and thus reduce the delirium and slow the heart and respiration by lessening the muscular movement. Moreover, the tissue waste is much increased in fever, and at the same time the food absorp- tion is less than normally, so that many of the symptoms may be due to 148 ORGANIC DRUGS ACTING AFTER ABSORPTION. starvation of the tissues. The food- value of alcohol is unchanged by the presence of fever (Ott) ; it demands less energy from the digestive organs than fats and starchy foods, and has a higher value as a producer of energy than sugar. It cannot supply the place of the nitrogenous foods, but given along with them, may lead to a greater economy of the tissues. It is to be remarked that according to Neumann alcohol fails to have this effect, at any rate in normal individuals, until it has been given for several days, so that if it is to be used as a food, it ought to be given early in the disease. Strong wines or diluted spirits are generally employed here and ought to be given in small quantities frequently. Alcohol was formerly advocated especially in septic con- ditions, and here it may be of value on the same grounds as in acute fevers, although it does not seem to have any specific action in septic disease, as was once believed. A protest has recently been raised against the use of alcohol in these cases, on the ground that animals subjected to alcohol succumb more readily to infection than controls which have received no treatment, and this has been shown to be true even when the dose of alcohol was proportionate to that often advised in the treatment of these cases in man (Laitinen). This is undoubtedly an objection of great weight, but it must not be forgotten that though alcohol may be deleterious in this way, this may be more than com- pensated for by its value as a food, and by its narcotic effects allaying the nervous irritability and promoting sleep ; this narcotic action may very well be conceived to be of benefit to man, while actually preju- dicial to animals. In some chronic forms of nervous disease alcohol may also be of value, although its administration must always be guarded, owing to the tendency to the formation of the alcohol habit. Thus, in some forms of melancholia and of neuralgia it gives relief, partly probably through its depressant action on the brain and partly from its local action on the digestion. Some authorities recommend the use of alco- hol in small quantities in cases of distress of mind from any cause, such as grief, business anxiety or depression, and undoubtedly alcohol improves these conditions by its narcotic action on the brain. But the danger of the alcohol habit is so great, that many physicians refuse to take the responsibility of prescribing the drug in these cases. In chronic conditions of cachexia and loss of flesh in general, and during convalescence, alcoholic preparations are often advised simply as foods, and in these cases the ales, beers and porters are generally to be preferred to the others, provided always that the stomach is not irritated by them, as they contain other food-stuffs of value in addition to the alcohol. In poisonous snake bite, alcohol is generally administered in enor- mous quantities, either as whiskey or brandy, but it seems open to question whether it is really of value in these cases, and its action on the normal tissues certainly gives no indication for its use here. Alcohol is of value as a mild hypnotic, a comparatively small quan- ALCOHOL. 149 tity taken before retiring being often sufficient to secure quiet and refreshing sleep. Beer or spirits and water is generally used for this purpose. Brandy has a certain reputation in the treatment of the milder forms of diarrhrea, while the other spirits have no effect in this condi- tion. The means by which this effect is accomplished are unknown. In the prescription of alcohol, the ordinary spirits, brandy or whis- key, are very much more frequently advised than the purer prepara- tions, as the latter are more apt to pall upon the taste of the patient. Both of these spirits ought to be diluted with at least an equal quan- tity of water. The wines are more used in chronic conditions, although diluted spirits may be advised here also. Beers are employed only in debility unaccompanied by gastric symptoms. Alcohol can be given to children in relatively larger quantities than to adults, and again in old age no such reduction in the dose is required as in the case of many other drugs. Where a tolerance for alcohol has been established, the dose has often to be more than doubled in order to have any effect, and in acute febrile conditions very large quantities of alcohol are often given without intoxication, though it seems ques- tionable whether an equally beneficial result could not be attained with much smaller doses. In gastric irritation, most preparations of alco- hol are contraindicated, but champagne is often of benefit in checking vomiting, especially that of pregnancy and of seasickness, this effect being due to the carbonic acid, not to the alcohol. In nephritis and other inflammatory conditions of the genito-urinary tract, alcohol is generally avoided on account of its supposed effects on the epithe- lium. In regard to the habitual use of alcohol by healthy persons all authorities agree that it is a luxury, that it is entirely unnecessary for the growth and maintenance of the body, but that taken in moderate quantities it is harmless, except from the danger that this may lead to the habit being formed. The habitual indulgence in alcohol to excess is more easily intelligible than some other chronic intoxications, for, unlike nicotine, alcohol is taken not only for its local effects on the organs of taste and on the mucous membranes of the mouth and stomach, but also for its action on the brain in numbing the con- sciousness of unhappiness, and this weakening of the higher sensibilities by drink is generally the object sought by the drunkard. He finds that under alcohol his habitual depression disappears, and he loses the sense of degradation and remorse which possesses him when sober. The depression returns in exaggerated form after the effects of the drug have passed off, but it can be removed again by the same means, and in this way the habit is formed, each successive dose being rendered necessary by the depression produced by its predecessor. This descent into chronic drunkenness is facilitated by the lessening of the self-control owing to the action of alcohol on the brain. The victim may form the best of resolutions, but his impaired will power and self-control are unable to carry them out. 150 ORGANIC DRUGS ACTING AFTER ABSORPTION. The symptoms of Chronic Alcoholism are unfortunately common, but may be treated better in detail in connection with various forms of dis- ease, with which they are associated more closely than with the effects produced by the medicinal use of the drug. The earliest symptoms are generally observed in the stomach, throat and larynx, and consist of a chronic catarrh, which is often accompanied by skin affections, such as injection of the cutaneous vessels (especially of those of the face), acne or pustular eruptions. The irritation spreads from the stomach to the liver and kidney, and produces fatty degeneration and necrosis of the cells, followed by increased growth of the interstitial connective tissue, and cirrhosis of these organs. The fatty degenera- tion is also found in the arterial walls throughout the body, and causes atheroma and arterio-sclerosis, which may lead to small aneurysmal dilatations, ecchymoses, or apoplexy. The heart undergoes more or less fatty change, which is accompanied by dilatation and weakness. In the central nervous system, the nutrition is imperfect owing to the vascular changes, but in addition to this, alcohol has a special action on the neurons, which is betrayed by the disappearance of the chro- matin granules, and eventually by shrinkage of the whole cell. The dendrites show moniliform enlargements along their course, and in the later stages the finer dendrites disappear entirely. These alterations in the central nervous system lead to impairment of memory, self- control and the other higher mental processes. Tremor, convulsive attacks, hallucinations and mania are eventually followed by idiocy and paralysis in the worst forms of the disease. The peripheral nerves seem to be acted on directly as well as through the changes in the centres, for neuritis has been frequently observed, ending in local paralysis. A form of amblyopia commencing by atrophy of the retinal ganglion cells and later extending to the fibres of the optic nerve has recently received some attention ; it is much more readily elicited by methyl than by ethyl alcohol. A characteristic result of chronic alcoholism is delirium tremens, an acute attack of insanity, which is liable to occur after any shock, such as hemorrhage or acute disease, but which is said to be also produced by the sudden withdrawal of alcohol, and sometimes occurs without any apparent immediate cause. It is characterized by tremor, perspiration, sleeplessness, fear, ex- citement and hallucinations of the various senses, which differ from many other hallucinations of insanity in consisting of the multiple appearance of the same object. These objects are often animals, such as snakes, rats, dogs, but the hallucinations are not confined to those of sight, for whispering voices are complained of not infre- quently. The more severe forms of chronic alcoholism are confined almost entirely to the drinkers of undiluted spirits. Beers and wines seldom have any distinct action on the brain in themselves, unless spirits are also indulged in. The abuse of the weaker preparations of alcohol is always liable to lead to that of the stronger, however, as tolerance is ALCOHOL. 151 established and the former lose their effect. The combination of spirits and malt liquors is said to be more liable to produce delirium tremens than the abuse of either alone. The disastrous effects of the abuse of alcohol are seen in the statistics of the hospitals, prisons, and asylums, and unfortunately these show an increase in the number of victims almost every year and in nearly all countries, but more especially in those in which the population is addicted to spirits. In Prussia, in 1886-1888, 11 per cent, of the cases admitted to the insane asylums were diagnosed as directly due to alcoholic excess, while in one of the Berlin asylums the enormous per- centage of 47.4 of the admissions were found to be addicted to alcohol. In France, in 1888, one eighth of the cases of suicide were due to alcoholic excess. In Paris, 72 per cent, of the convicted criminals in one year were found to be chronic alcoholists, while the proportion in Berne Canton was about 40 per cent. These numbers are officially certified to be correct, but give only an imperfect idea of the deplor- able results of alcoholic abuse, as only the more extreme cases come under the categories of criminals or lunatics, and the enormous num- ber of cases of disease directly caused or aggravated by the lesions due to alcohol escapes recognition. At the same time, it is beginning to be appreciated that chronic alcoholism itself is probably due to a mental defect, so that in a certain number of these cases of insanity and crime, the over-indulgence in alcohol must probably be considered a symptom and not a cause. Attempts have been made of late years to demonstrate that the effects of alcohol are hereditary, that the chil- dren of alcoholists supply a larger proportion of cases of insanity and crime than those of the rest of the population. The belief is widely entertained among biologists, however, that acquired characters such as alcoholism are not inherited directly, but can only affect the nutri- tion of the offspring. It would seem more probable, then, that the alcoholic excesses of the parent have no direct effect on the offspring, except in their nutrition at birth, but that the mental defect which leads to alcoholic excess in the one generation is inherited and leads to crime or insanity in the next. The deleterious effect of the alcoholic habit in the parent on the nutrition of the offspring is a well- established fact. It has been shown experimentally by Hodge, who states that only a small percentage of the puppies born of parents treated with alcohol survive, and further that they are peculiarly liable to infectious disease, such as distemper. The treatment of acute alcoholic intoxication is to evacuate the stom- ach by means of the soft elastic tube. The patient ought to be put in bed and kept warm, as there is a tendency to a marked fall in the body temperature. In case of great congestion of the brain, cold may be applied in the form of ice-bags to the head, and some authorities recommend bleeding. In cases of extremely deep unconsciousness, nervous stimulants, such as caffeine or strychnine, may be had recourse to, and, as a last resort, artificial respiration. 152 ORGANIC DRUGS ACTING AFTER ABSORPTION. Chronic alcoholism is to be treated by the withdrawal of the poison, and this is best done gradually, as the immediate stoppage may lead to delirium tremens. It is often necessary to incarcerate the patient in some retreat. A large number of drugs have been advocated in these cases, some of them such as opium acting as substitutes for alcohol, others (capsicum) replacing the local action on the stomach. The use of opium and other narcotics may however lead to a craving for these which is quite as serious as the original condition. Another method of treatment, which appears to be successful in some cases, is the ad- dition of nauseating drugs such as ipecacuanha or apomorphine to the alcohol which is supplied to the patient. The association of nausea with liquor eventually becomes so strong that alcohol in any form becomes distasteful. The organic lesions must be treated individ- ually. The treatment of delirium tremens generally consists in the use of chloral or opium to lessen the excitement. It is often necessary, or at any rate advisable, in these cases to allow small quantities of alcohol, as the sudden withdrawal may aggravate the condition. BIBLIOGRAPHY. An admirable critical survey is given by Abel, Atwater, Chittenden and Welch, in Physiological Aspects of the Liquor Problem, Boston and New York, 1903. G. Rosenfeld. Der Einfluss des Alkohols auf den Organismus. Wiesbaden, 1901 (very complete bibliography). Binz, Jaksch. Verhandl. des VII. Congress f. innere Medicin, 1888, pp. 70, 86. Bunge. Die Alkoholfrage, Leipzig, 1887. Jacquet. Die Stellungsnahme des Arztes zur Abstinenzfrage, Basel, 1896. Pohl Arch. f. exp. Path. u. Pharm., xxxi., p. 281. Berkeley. Brain, xviii., p. 473. Brandl, Scanzoni, Farnsteiner. Ztschr. f. Biol., xxix., p. 277 ; xxxiii., pp. 462, 475. Chittenden and Mendel. Amer. Jour., of the Med. Sciences, 1896, p. 35. Kraepelin. Ueber die Beeinflussung einfacher psychischer Vorgange durch einige Arzneimittel, Jena, 1892. And in Kraepelin's Psych ologische Arbeiten, i.-iv., passim. Jacquet. Arch, de Pharrnacodynamique, ii., p. 107. Ndcke. Deutsch. Arch. f. klin. Med., xxv., p. 416. (Delirium tremens ) Baer. Arch. f. [Anat. u.^Phys., 1898, p. 283. Liepmann. Arch. f. Psychiatrie, xxvii., p. 172. Gudden. Ibid., xxviii., p. 643. Radzikowski. Pfliiger's Arch., Ixxxiv., p. 513. Spiro. Munch, med. Woch., 1901, p. 1871. Boedecker. Arch. f. Psychiatrie, xxvii., p. 810. Chittenden, Mendel and Jackson. Amer. Journ. of Physiol., i., p. 164. Zuntz and Magnus-Levy. Pfliiger's Arch., xlix., p. 438; liii., p. 544. Deltio. Centralbl. f. Nervenheilkunde und Psychiatrie, 1895, p. 113. Brauer. Ztschr. f. Physiol. Chem., xl., p. 182. Dieballa. Arch. f. exp. Path. u. Pharm, xxxiv., p. 154. Weissenfeld. Pfliiger's Archiv, Ixxi., p. 60. Wendelstadt. Ibid., Ixxvi., p. 223. Singer. Arch, internat. de Pharmacodyn., vi., p. 493. Schumberg. Arch. f. [Anat. u.] Phys., 1899, Suppl., p. 289. Sche/er. Arch. f. exp. Path. u. Pharm., xliv., p. 24. Hellsten. Skand. Arch. f. Phys., xvi., p. 139. Schnyder. Pfliiger's Arch., xciii., p. 451. Rosemann. Pfliiger's Arch., Ixxvii., p. 405; Ixxxvi., p. 307. Neumann. Arch. f. Hyg., xxxvi., p. 1 ; xli., p. 85. Atwater and Benedict. U. S. Dept. of Agriculture Exper. Station Bulletin No. 69. Ott. Arch. f. exp. Path. u. Pharm., xlvii., p. 267. ETHER AND CHLOROFORM. 153 Grehant. Journ. de 1' Anatomic, xxxvi., p. 143. Abbott. Journ. of Exp. Med., L, p. 447 ; Univ. of Pennsylvania Med. Bull., Sept., 1902. Laitinen. Ztschr. f. Hygiene, xxxiv., p. 206. Acta Societat. Scient. Fennic., xxix. Rubin. Journ. of Infectious Diseases, i., p. 425. Friedberger. Berlin, klin. Woch., 1904, p. 242. Hare. Trans. Assoc. Amer. Physicians, 1903, p. 391. Birch-Hirsch/dd. Arch. f. Ophthalraologie, lii., p. 358 ; liv., p. 68. Paton and Eason. Jour, of Physiol., xxvi., p. 166. Beebe. Amer. Journ., of Physiol., xii., p. 13. Harrington. Boston Med. and Surg. Journal, 1903 (germicidal action). Weigl. Arch. f. Hygiene, xliv., p. 273 (germicidal action). Wirgin. Ztschr. f. Hygiene, xl., p. 307 ; xlvi., p. 149 (germicidal action). Hunt. Johns Hopkins Hospital Bulletin, xiii., 1902. Buller and Wood. Journ. of Amer. Med. Assoc., 1904, II. 2. General Anaesthetics Ether and Chloroform. The term general anaesthetics is employed to indicate substances used to produce unconsciousness sufficiently complete to allow of surgical operations being performed. In the history of medicine there are repeatedly obscure allusions to substances used for this purpose, but it was not until the end of the first half of the nineteenth century that the era of surgical anesthesia really opened. In 1798, Davy advised the use of nitrous oxide as an anaesthetic, but no practical use was made of his suggestion, and Wells may be said to have rediscovered this property of the gas in 1844, though his efforts to introduce it into general use met with no greater success than Davy's. Long used ether in 1842 1843 in surgical operations, but did not give any publicity to his dis- covery, and the honor of demonstrating publicly the practical use of ether in surgery must be awarded to Jackson and Morton in 1846. In 1847, Simpson introduced chloroform to the medical profession as a substitute for ether, over which he supposed it to possess several ad- vantages. Its pharmacological action had been investigated some months earlier by Flourens, but Simpson appears to have made his investigations quite independently. Chloroform soon ousted ether in popular favor in Europe, and although in America a considerable number of surgeons continued to use it, ether had practically fallen into complete disuse throughout Europe, save in Lyons, until a few years ago. The continually increasing number of accidents in chloro- form anaesthesia has, however, caused a reaction to set in in favor of ether, and it seems probable that it will once more be reinstated as the rival, and perhaps as the superior, of chloroform throughout the world. Even in 1880, however, Kappeler could write that in Germany chlo- roform was used exclusively. Many attempts have been made to introduce other substances of the methane series as substitutes for the two generally recognized anaes- thetics, but as yet no other has attained popular favor. Soon after the introduction of ether and chloroform, nitrous oxide gained a perma- nent footing as an anaesthetic for short operations. These anaesthetics are invariably given by inhalation and not by the stomach, as it is found that the exact depth of the narcosis can be 154 ORGANIC DRUGS ACTING AFTER ABSORPTION. much more easily controlled by the former method. Both the absorp- tion and excretion of these drugs occur almost entirely by the lungs, according to the ordinary physical laws of the absorption of gases by fluids. The more concentrated the vapor of chloroform in the lungs, the greater is the quantity absorbed into the blood and the deeper the narcosis. By regulating the proportion of the vapors in the air in- haled, therefore, an anaesthesia of any desired depth may be induced. The degree of narcosis and of danger is not indicated by the actual amount of the anaesthetic which has been used, but by the concentra- tion of the vapors which have been inhaled ; one patient may, in the course of a long operation, inhale and again exhale many ounces of chloroform without danger, while another may be thrown into a position of extreme peril by the inhalation of a few drops of chloro- form in concentrated vapor. Symptoms. The action of chloroform and ether may be divided into three stages : 1, that of imperfect consciousness; 2, that of ex- citement ; 3, that of anaesthesia. The first effect of their application is a feeling of asphyxia, which is especially marked in the case of ether, and of warmth of the face and head and eventually of the whole body. The senses become less acute, the patient seeming to see only through a veil of mist, and the voices of those in the immediate neighborhood appearing to come from a dis- tance. Ringing, hissing and roaring in the ears, and a feeling of stiff- ness and of inability to move the limbs herald the approach of uncon- sciousness. With the exception of the first feeling of suffocation, the sensations are generally pleasant. During this stage the face is gener- ally flushed, the pupils enlarged, the pulse is somewhat accelerated, and. the respiration may be rendered irregular by the sense of suffoca- tion, or may be slightly quickened. Even at this early stage sen- sation is blunted. The second stage of excitement varies extremely in different indi- viduals. In some cases, especially in children, it is entirely absent, and in others its presence may be indicated merely by tremor, by the stretching of the limbs, or by irregularities in the respiration, but in the majority of cases of anaesthesia it is much more marked. It often begins by movements of the arms, designed either to push away the inhalation mask or to enable the patient to rise ; soon his other mus- cles are involved in the movement ; he struggles, shouts, sings, groans, or bursts into laughter. The movements are not generally uncoor- dinated, but are evidently the result of some dream-like condition of the consciousness, and these dreams are often connected with the opera- tion or with the surroundings of the patient before the inhalation began. They are, of course, determined largely by his natural mode of thought one person prays aloud and sings hymns ; another abuses the surgeon, the hospital and all his recent surroundings,while yet another is overcome with the fear of impending death and laments his unfortunate position. In this stage the pulse is generally quickened, the skin is flushed and ETHER AND CHLOROFORM . 155 often cyanotic, the respiration is extremely irregular from the strug- gling, and the pupil continues somewhat dilated. If the anaesthetic be pushed, however, the movements soon become less powerful, the muscles relax and the stage of anaesthesia sets in. In the third stage, the face assumes a calm, death-like appearance from the relaxation of the muscles, the pupils contract somewhat and do not react to light. The reflexes disappear, one of the last to go being the closure of the eyelids on touching the cornea. The pulse is generally somewhat slow and weak ; the face is pale in chloro- form anaesthesia, but may be suffused and cyanotic after ether. The respiration is slow and shallow, but regular. This stage of anaesthesia may be kept up for hours without much change by the repeated inha- lation of small quantities, although the pulse tends to become weaker and the respiration shallower unless the greatest care be exercised, and the body temperature invariably sinks. When the administration ceases, the patient passes again through the excitement stage, which, however, is not generally as violent, although it may be more pro- longed, and then often sinks into sleep, which lasts several hours. Not infrequently, however, instead of sleep, nausea, giddiness and vom- iting continue for some time after the recovery of consciousness. In surgical anaesthesia, the third stage is often interrupted by short intervals of semi-consciousness and slight excitement if the adminis- tration of the drug be occasionally interrupted, as is sometimes ad- visable in prolonged operations. The use of these drugs is so widespread, and the indications of danger in anaesthesia are so important that a more detailed account of the alterations observed during their use in the human subject may be inserted here. The pulse is often somewhat accelerated before anaesthesia, owing to the anxiety and nervousness of the patient, and in the first, and still more the second stage, a further acceleration may occur from the same cause, although in other instances marked slowing of the pulse may set in here from reflex stimulation. When the stage of anaesthesia is reached, the pulse becomes slower and weaker than normally, and this change increases with the depth of the anaesthesia produced. It re- mains perfectly regular, however, in ordinary cases, and, in fact, un- less the anaesthesia has reached an extremely dangerous stage. In very prolonged, deep anaesthesia the weakness of the pulse may give rise to anxiety, especially if the temperature of the body is very low. The respiration is generally fairly regular until the second stage, save that the breath may be held for some time owing to the choking sensation, and a deep gasp may follow ; coughing is occasionally met with, especially in the first stage of ether anaesthesia. In the second stage, the respiration is extremely irregular when the excitement is violent. The respiratory muscles are involved in the general convul- sive movements, so that no air whatever can enter the lungs for several moments, and then several deep gasps may follow and load 156 ORGANIC DRUGS ACTING AFTER ABSORPTION. the blood with concentrated vapor. Daring the third stage the res- piration becomes regular but shallower and slower than before the anesthetic was applied, and if the operation be prolonged, the weak- ness of the respiration may give rise to alarm. Large quantities of saliva and mucus may hinder the respiration and require removal, and a common occurrence is the production of snoring from the falling back of the tongue, and this may also require attention. The behavior of the pupil is of some importance in anaesthesia. During the first and second stages it is generally somewhat dilated, but as soon as complete unconsciousness is attained, it becomes rather narrower than it is normally. As the patient recovers, the slight dil- atation recurs, and if the respiration and circulation be dangerously weak, this dilatation also occurs in most cases. Dilatation of the pupil in the stage of anaesthesia, therefore, indicates danger, unless it is accompanied by symptoms of returning consciousness, such as reflex movements and vomiting. Other eye symptoms which occur in some cases are squinting and more or less rhythmic movements of the eyeball. In the beginning of the narcosis the pupil is generally directed upward and is covered by the upper lid as in ordinary sleep, but later it returns to the normal position ; curious rolling movements, which are quite independent in the two eyes, often make their appearance (Kappeler, Hogyes). The hyper secretion of saliva and of bronchial mucus is much more marked in ether than in chloroform anaesthesia. Vomiting occurs so frequently during anaesthesia that it may be looked upon rather as one of the attendant phenomena than as an accident. It may set in prac- tically at any time, but is more often seen in the late than the early stages, and more frequently when the anaesthetic is applied soon after a meal than when the stomach is empty. Action. The action of ether and chloroform on the Central Nervous System is evidently similar to that of alcohol, although the phenomena habitually elicited in the use of the former are very rarely produced by the latter. In all three intoxications, however, there may be observed the stages of lessened consciousness, of excitement, and of total uncon- sciousness. Alcohol was formerly administered in very large quantities to allow of surgical procedure, and ether has not infrequently been used as a habitual intoxicant. These anaesthetics produce the same progressive paralysis of the cen- tral nervous system as alcohol, commencing with the highest cerebral functions, those of self-control, and passing downwards through the lower intracranial divisions. The spinal cord is affected before the medullary centres, which are the last part of the central nervous sys- tem to become paralyzed. Some authorities believe that the motor areas of the brain are first stimulated before being paralyzed, but it is unnecessary to enter upon this question here, as it has been discussed under alcohol. The wilder excitement of chloroform and ether may be due to the greater irritation which they excite in the periphery. It may be remarked that the depression of the motor areas has been ETHER AND CHLOROFORM. 157 FIG. 5. shown experimentally in the case of chloroform and ether, a much stronger electric stimulus being necessary to produce movement of a limb after these drugs than before them ; their excitability by the elec- tric current has not been tested, however, during the excitement stage. The anaesthesia is not produced equally rapidly throughout the body, the back and the extremities first be- coming insensible, then the genital or- gans and rectum and, last of all, the parts supplied by the trigeminus. The reflexes of the spinal cord are said to be first increased by ether and chloro- form and then depressed and paralyzed, but the primary increase is of very short duration and, in fact, it is open to ques- tion whether it occurs at all. It would seem that ether and chloroform tend to depress the sensory functions before the motor. For Bernstein found in some cases that if chloroform were excluded from a section of the spinal cord by destruction of part of the pia mater, reflexes could be elicited in other parts of the cord by the irritation of sensory nerves whose cells lay in the protected area, while irritation of nerves, the cells of which were exposed to the chloroform, had no effect (Fig. 5). In the protected area there were, of course, both motor and sensory cells, and an im- pulse reaching the protected sensory cell was transmitted to the neighboring and also to more distant motor cells. An impulse reaching the exposed sen- sory cell, on the other hand, was not transmitted to the motor cells, although these were shown by the first part of Diagram of the spinal cord. A-B^n thp pvnprimpnf to V>p rnmnVilp nf cfirrmln of the corcl exposed to the action of chlo- , CapaOLC OI StimUla- roform, S-C part unaffected. A sensory tion. Later, however, the motor Cells pr^sion traveling by the posterior root . V-V.AAO fibre # does not elicit a reflex movement, are also paralyzed, as IS shown by but one reaching the cord through the un. i , . / . i -IT . nn affected root E causes reflex impulses, Stimulation OI the COrd having: no enect, which may be sent out by the motor cells i ,1 .... .,, . F, Fin. the unaffected area, or bv F' F' even When the respiration IS Still active, in the poisoned area. The cells of ;the an- T?1/A/-.fw/^ol n4-Jw,,,l*^ ^f 4-V. U 1 terior horns F. F' and the dendrites sur- Llectncal Stimulation Ot the Cerebral rounding them are, therefore, intact after motor areas produces movement for some po? n r t eflex arc is interru P ted atsorae other time after sensation has been lost, but as the anaesthesia becomes deeper, their irritability disappears. Finally the medullary centres are also paralyzed by the anaesthetic. Some authorities have stated that they are first stimulated directly by chloro- form and ether, but the evidences for this will be discussed later (page 158 ORGANIC DRUGS ACTING AFTER ABSORPTION. 162). The medullary centres are liable to be affected by reflex stimu- lation up to the moment at which they cease to send out impulses, for the respiratory centre responds to stimulation of the superior laryn- geal nerve as long as the respiration continues. It is possible that the motor cells are not directly paralyzed by the drug, but can only send out impulses received from the sensory cells, and that the paralysis of these is the cause of the asphyxia. Shortly stated, the direct action of chloroform and ether on the cen- tral nervous system is a descending depression and paralysis which affects the medullary centres last of all, and which probably affects the sensory and receptive functions sooner than the motor ones. The action of chloroform and ether on the Respiratory Centre is partly direct and partly indirect. In the first stage, the respiratory movements may be slowed or stopped temporarily by a reflex action set up by the irritation of the terminations of the trigeminus in the nose and throat and of the pneumogastric in the larynx and bronchi, but this interruption is only of short duration (Fig. 6). During the FIG. A B G t Tracings of the blood-pressure (upper) and of the respiration (lower) of a cat at the beginning of ether inhalation. A, normal respiration. At B, ether inhaled, and there follows an immediate slow- ing of the respiration (reflex inhibition) culminating in gasping at C. The respiratory traciug then resumes its normal appearance except for some slowing (central). second stage the respiration is often rendered irregular by the convul- sive struggling, which produces alternately periods of asphyxia and deep gasping movements. During the third stage, the respiration is regular and no reflex disturbance occurs, because the sensibility is so dulled that the continued irritation of the nerve ends causes no reflex response. In this stage, however, the direct action of the drug on the centre makes itself manifest in the slow and shallow respiratory move- ments. If the drug be pushed, the weakness and slowness of the movements increase, until the respiration ceases entirely from paralysis of the centre ; in addition to its direct action on the centre, chloroform depresses the respiration in deep anaesthesia by inducing anaemia of the medulla through its effects on the circulation. In man and the dog and cat the respiration is gradually extinguished, but in the rabbit the final standstill is preceded by very rapid and extensive respiratory movements. The effects of the anaesthetics on the Circulation are complicated by the respiratory action, and in order to arrive at any satisfactory con- clusions as to the changes in the heart and vessels, it is therefore neces- sary to examine their action while the aeration of the blood is carried on artificially, when the effects are seen to be partly direct and partly indirect. The first change observed in the blood-pressure tracing, ETHER AND CHLOROFORM. 159 after chloroform or ether is often a slowing or even a temporary stand- still of the heart, due to reflex stimulation of the inhibitory centre from the irritation of the air passages ; but in other cases a short rise in the blood-pressure is seen from a similar reflex action on the vaso- motor centre and this may be accompanied by extreme acceleration of the pulse arising from the general excitement. Later, however, a fall FIG. 7. lJtH ^ J ^^^^^-Artrt^^ Gradual fall of the blood-pressure in a cat during anaesthesia with dilute chloroform vapor. At A, normal pressure. B, inhalation commenced and the pressure slowly falls soon afterwards. C, blood- pressure 5 minutes after B. D, 10 minutes after B. E, 13% minutes later. At E, the respiration has ceased, but the blood-pressure is still fairly high and the pulse is satisfactory. Below the time is marked in seconds. in blood-pressure is observed, and afterwards a distinct slowing of the heart. Eventually, if the administration be carried far enough, the blood-pressure falls to zero and the heart ceases to beat. The way in which this fall in the blood-pressure is produced has been the subject of prolonged discussion, but it is now generally recognized that the weakness of the heart is the chief factor and that along with this there FIG. 8. Sudden and dangerous fall in the blood-pressure from the inhalation of too concentrated vapor of chloroform during anaesthesia in a cat. At A the concentrated vapor began to be inspired. At B the blood-pressure had fallen to about one third of the height at A, and the pulse was so weak as to be scarcely perceptible. The chloroform mask was removed, and at C artificial respiration was com- menced when the pulse rapidly improved in strength and the pressure began to rise. is dilatation of the peripheral vessels. The blood-pressure in man has been found to be reduced by chloroform even in the earlier stages, and in deep anaesthesia the fall may be very marked. Under ether the pressure rises slightly in the first and second stages, partly from the reflexes arising from the local irritation, and partly from the muscular movements. During complete anaesthesia it falls again to slightly above the normal or a few millimetres below it, but never reaches a 160 ORGANIC DRUGS ACTING AFTER ABSORPTION. point indicating grave circulatory disturbance (Blauel, Cook and Briggs). Heart. The frog's heart under chloroform or ether beats more slowly and more weakly, and at the same time undergoes a certain amount of dilatation, all owing to the paralyzing effects of these drugs on the cardiac muscle. About 48 times as much ether as chloroform is required to affect the frog's heart, however, and in order to bring it to diastolic standstill 36 times as much ether as chloroform must be added to the blood. The effects on the mammalian heart in deep anaesthesia are very similar. The slowing is not so marked, however, as the weakness and the dilatation, so that the rhythm of the pulse does not indicate the extent to which the heart is affected. The auricles are acted on by smaller quantities than the ventricles, and the former may be rendered so weak as to give practically no movement to an attached lever long FIG. 9. Myocardiographic record of the movements of the right auricle (upper tracing) and right ventricle (lower tracing) of the dog daring the inhalation of concentrated chloroform vapor. During systole the lever attached to the auricle moves from D' to ^sleep, but since the discovery of chloral and its congeners it is used less frequently. These fail entirely to replace it, however, where the sleeplessness is due to pain, while, on the other hand, they are more efficacious in some conditions of excitement. Not infrequently opiumj land chloral are prescribed together for this purpose, and the combi-j \nation acts more efficiently than either of the drugs alone. Each is, of course, prescribed in considerably smaller amount than if adminis- tered separately. Opium is less efficient than chloral when there is apparently an increased activity of the motor functions of the brain, as in wild delirium and mania, and sometimes seems to increase the excite- ment even, but this general statement is subject to numerous excep- tions, and morphine is still largely used in many such disorders. In the true convulsive diseases, such as tetanus, epilepsy and chorea, chloral is preferable. The beneficial effect of morphine in many acute febrile conditions is undeniable, and, as in the case of alcohol, is due to its lessening the pain and discomfort of the patient and inducing rest. A good deal of difference of opinion exists as to the advisability of administering opium or morphine in these conditions, and there is no question that the routine treatment of fever by narcotics is to be deprecated ; but on the other hand, the restlessness and discomfort may in itself aggravate the disease, and morphine is distinctly indicated under these circumstances. The preparations chiefly used to relieve pain and promote sleep are the extracts, laudanum, opium pill, or compound soap pill, and the morphine salts and their solutions. The latter may, of course, be ad- . ministered hypodermically. ^\ ] In Respiratory Disorders, opium and morphine are largely used for ^" 1 - u ~ : - e ff ec t s on the centre. Where it is desirable to lessen its irrita- bility, as for example in excessive cough and dyspnoea, opium may be indicated. On the other hand, when there is a profuse expectora- tion, the irritability of the centre cannot be lowered without danger, and opium is contraindicated. Opium gives relief in cases of asthma, but there is always danger of inducing the habit. Opium is often combined with expectorants in the treatment of cough, and a large number of suitable preparations are provided in the pharmacopoeias, such as paregoric, Dover's powder and other prepa- rations containing ipecacuanha, liquorice mixture, the compound mor- phine powder (U. S. P.), the ammoniated tincture, the compound OPIUM SERIES. 223 tincture of chloroform and morphine, the pills of ipecacuanha and squill (B. P.), the lozenges and the codeine preparations. .Codeine is often preferred to morphine in these cases, because it reduces the ex- - citability of the respiratory centre with less marked cerebral depression,^ This is also true of the new artificial alkaloids, heroine and dionine, which have enjoyed some popular reputation in late years. Impartial investigators of these drugs have generally failed to obtain better results from them than from codeine and morphine, and further inves- tigation is required before they can be recommended as superior to the /.older and unpatented alkaloids. In Peritonitis and Intestinal Disorders, opium is indicated doubly 5 Xftrst, for its general action in allaying pain and restlessness ; and secondly, for its special action in lessening the movement of the intestine. Opium is preferable to morphine for these purposes because it lies longer in the bowel, and therefore evolves a stronger action there than on the rest of the economy. In colic, especially lead colic, it often relieves the pain without increasing the constipation and seems to allay the spasm of the bowel without stopping entirely its peristalsis. In diarrhoea opium may be given to check the excessive peristalsis, though in the severer forms of dysentery it generally fails to have this effect, and in septic purging is rather to be avoided. In perforation and hemor- rhage from the bowel, opium is the most efficient of all remedies, as it allows adhesions or clots to be formed by checking movements of the intestine, which would provoke further leakage. The B. P. offers a number of preparations specially designed for use in intestinal disorders and especially in diarrhoea, such as the com- pound kino powder, the compound chalk powder, the lead and opium pill, and the compound lead suppository and morphine suppository. Instead of these the tincture,- extract or other simple preparation may, i of course, be used. In Haemorrhage, where the bleeding point cannot be reached, opium * or morphine is most valuable. This is not from any direct effect on the vessels or blood, but because it f) allays the restlessness which follows the loss of large quantities of blood and thus allows the blood to clot in the ruptured vessel. The same preparations are suitable here as for pain. In Vomiting morphine is sometimes used in small quantities, but it seems doubtful whether with any benefit. An injection of 10 mg. (-i gr.) of morphine often facilitates the use of ether in Anaesthesia and is a routine practice in some clinics. ^ In others 0.3 mg. hyocine is added, and very small quantities of ether are required afterward. Opium has been used instead of quinine in Malaria, and though it can- J^not be said to replace the latter, has a distinct effect in some cases appar- ently. Of course, symptoms may arise in malaria as in other diseases in which opium is specially indicated, but apart from this, cases of malaria of old standing seem to be benefited by opium with or without quinine. Opium or morphine has sometimes been used in Diabetes with good > 224 ORGANIC DRUGS ACTING AFTER ABSORPTION. effects ; for though the glycosuria seldom disappears under its use, it is lessened in some cases (Kaufmann). Codeine has been advised instead of morphine in this disorder, as it is less likely to cause constipation and gastric disturbance. Lastly, opium, is used as a Diaphoretic, and for this purpose it is gen- erally combined with ipecacuanha and prescribed as Dover's powder. Although in itself it has little or no diaphoretic action, ^^um rnjiy augment the effects of ipecacuanha through dilating the skin vessels. Opium and its alkaloids have no effect applied to the skin, and the plasters, ointments and other similar preparations are quite superfluous. Codeine is much less often used than morphine in therapeutics. It is of comparatively little value in allaying pain or excitement, but has been found of benefit in the sleeplessness of melancholia. It is used not infrequently as a sedative in cough, and, as has been stated, in diabetes. There seems less liability to the formation of the codeine habit, and it has been suggested as a substitute for morphine in mor- phinornania, but has not proved efficient in this condition. Opium and morphine are contraindicated in very young children, in whom even minute quantities often produce the most alarming symptoms of poisoning. Even one drop of laudanum is said to have been fatal to a child under one year of age. In great weakness, especially in cases where the respiration is barely sufficient to aerate the blood, or where profuse expectoration is present, morphine has to be administered with the greatest care. In cerebral congestion and meningitis the opiates are generally contraindicated. It must be re- membered also that both opium and morphine are liable to disturb the digestion and to cause nausea and want of appetite, and that these may prevent their use in cases in which they would otherwise be suitable. In some persons opium invariably causes nausea and vomiting, either soon after its administration or while its effects are passing off. For this idiosyncrasy morphine may be substituted for opium, although this is often equally nauseating, or chloral and bromides may be prescribed with opium to prevent the unpleasant after-effects. Not infrequently, however, opium has to be avoided entirely. In all chronic painful diseases opium or morphine has to be given guardedly, on account of the risk of the formation of the opium habit ; the patient ought to be kept in ignorance of the drug used as far as possible, and it should be alternated with others. Of course, in cases of incurable, hopeless dis- ease, where life can only last a comparatively short time and is attended by severe suffering, this objection does not hold, and it may be neces- sary to administer morphine without stint and in ever-increasing quantity. Morphine and opium are often said to be contraindicated in Bright' g disease of the kidney. This seems to be due to the belief that mor- phine is excreted in the urine, which has now been shown to be erro- neous. There seems no reason to believe that morphine is harmful in these conditions, and in some forms of uraemia it has even been of considerable benefit. OPIUM SERIES. 225 Acute Poisoning with morphine or opium is one of the commonest forms of intoxication, with the exception of the alcoholic. It is often difficult to diagnose from other forms of unconsciousness, but the ex- treme contraction of the pupils give a clue, as a general rule, and if opium has been used, the breath often has the characteristic odor. The treatment is immediate evacuation of the stomach, whether the drug has been taken by the mouth or not, as even when injected hypo- dermically it is excreted into the stomach and may be reabsorbed. Emetics may be employed for this purpose, but often fail of effect owing to the depression of the medullary centres, so that where possible a stomach tube ought to be used in preference. The stomach should be thoroughly washed out at intervals, in order to remove every trace of the drug as it is excreted. As the respiration begins to fail, it is to be encouraged by irritation of the skin, either by dashing cold water on it, by the electric current, or by flipping it with towels. The violent flagellation formerly advocated with the view of en- couraging the respiration, served also usually to exhaust the nervous energy both of patient and attendant. When these means fail to keep up the natural breathing, it is necessary to resort to artificial respira- tion, either electrical or mechanical, and this ought to be continued as long as the heart continues to beat. Enormous doses of morphine and opium have been recovered from under this treatment. Numerous drugs have been advocated in acute morphine poisoning, and of these caffeine administered either hypodermically or in the form of strong coffee by the stomach seems the most satisfactory. A long controversy has been carried on as to whether atropine is to be considered an antidote to morphine and used in these cases. It is a stimulant to the medullary centres, and may, therefore, be used in small quantities ; but large quan- tities, such as have been advised by some authorities, are undoubtedly harmful, as atropine itself paralyzes the respiration when given in sufficient amount. Bashford states that the best effects are to be ex- pected from about 1.5 mg. (-fa gr.) of atropine and that more than this increases the danger of respiratory failure. In discussing this ques- tion too great weight has been laid on the results of animal experi- ment, which is not convincing in this case, as the effects of morphine are so different in man. Caffeine seems certainly more indicated than atropine, for it is scarcely possible to paralyze the respiratory centre with the former, which stimulates it equally strongly. Alcohol has been advised also, and as far as its local action is concerned, it may increase the respiration, but its direct action on the respiratory centre is similar to that of opium. Of late years permanganate of potash has been advised in case of morphine poisoning, because the poison is oxi- dized by it. A certain amount of poison in the stomach may be de- stroyed in this way, but the portion absorbed is unaffected by the per- manganate, and the method is less efficacious than the prompt and repeated use of the stomach tube. The hypodermic injection of per- manganate is, of course, entirely useless. Chronic Opium or Morphine Poisoning is a not infrequent condition, 15 226 ORGANIC DRUGS ACTING AFTER ABSORPTION. and, unfortunately, seems to be increasing rapidly. Among Eastern nations, especially in China and India, opium is smoked, and some of the morphine is carried over in the smoke and absorbed from the' res- piratory tract. This habit is rare in European peoples, among whom the drug is taken by the mouth, generally in the form of laudanum or of -~>ills, or is injected hypodermically as morphine hydrochlorate or sulphate. Of the three methods the first seems to be the least harmful, for in some parts of China the majority of the adult population seems to indulge in it without the serious results which are met with in the Western opium-eaters and morphinomaniacs. This result may be due in part to race, or to the fact that the opium-smoker never attains to the immense doses taken daily in the cases of the habit met with in Europe and America. In the beginning the quantity used is small, but as tolerance is attained, ever larger quantities are required to pro- duce any effect, until, as De Quincy states in his " Confessions of an English Opium-eater," 320 grains of opium may be required to stay the craving. The effects are generally described as stimulant, but it seems possible that they consist rather in depression of the sensibility, by which the unfortunate patient becomes unconscious of the miseries of his condition, and may accordingly be able to perform his duties and maintain appearances better than when deprived of the poison. The symptoms of the opium habit are exceedingly indefinite, and the diag- nosis is often almost impossible. The statements of the patient ought not to be taken into consideration, because these unfortunates seem to have lost all idea of honor and truthfulness. As a general rule they are nervous, weak in character and wanting in energy, and utterly unfit for work unless when supplied with the drug. The pupils are often contracted, the heart sometimes irregular, and tremors and un- steadiness in walking may be apparent. The appetite is bad and a considerable loss in weight occurs, and the movements of the bowels are irregular, constipation alternating with diarrhoea. Eventually melancholia and dementia may follow the prolonged use of opium, and especially of morphine. Some continue the habit for many years, however, and it would seem with comparative immunity. If mor- phine is injected habitually, evidence may be obtained from the small needle marks on the front of the body, which often give rise to mul- tiple abscesses of small size from carelessness in the disinfection of the syringe. When other evidence fails, it may be necessary to give a moderate dose disguised in some unusual way and to observe if it in- duces sleep ; in habitual users the ordinary dose will have little or no effect. The treatment of chronic morphine poisoning is not very promising. The will and self-control would seem completely paralyzed in many cases, and although the patient wishes to be freed from his enemy, he seems utterly unable to withstand the craving. The only means of treatment which promises success in most cases is the strict regime of an asylum or retreat, where the patient is kept under constant super- vision. The immediate removal of the drug often produces such in- OPIUM SERIES. 227 tense misery and depression as to seem actually dangerous ; but the withdrawal ought not to be too gradual, and ought to be complete after two or three weeks at the most. The patient has to be watched care- fully for long after he has apparently recovered, as relapses are ex- ceedingly common. The morphine habit has often been combated by the substitution of other drugs, such as cocaine, but the result generally has been that a new and even more dangerous habit has been substituted for, or often merely grafted on, the original. Numerous drugs have been proposed for the cure of morphinomania, but none of them seems to have the slightest effect. BIBLIOGRAPHY. The literature of opium is so immense that only a few of the more important phar- macological papers can be mentioned here. CL Bernard. Lefons sur les Ansesthesiques et sur P asphyxia. Paris, 1875. Gscheidlen. Untersuchungen aus dem physiologischen Laboratorium zu Wurzburg, ii., p. 1. Baxt. Arch. f. Anat. und Phys., 1869, p. 112. Filehne. Arch. f. exp. Path. u. Pharm., x., p. 442; xi., p. 45. Pfliiger's Arch., Ixii., p. 201. Loewy. Pfliiger' s Archi v, xlvii., p. 601. Araki. Ztschr. f. phys. Chem., xix., p. 422. Salvioli. Arch. f. Anat. und Phys., 1880, Supplement, p. 95. Bubnoffu. Heidenhain. Pfliiger's Arch., xxvi., p. 137. v. Schroeder. Arch. f. exp. Path. u. Pharm., xvii., p. 96. Witkowski. Arch. f. exp. Path. u. Pharm., vii., p. 247. Pohl. Arch. f. exp. Path. u. "Pharm., xxxiv., p. 87. AH. Berl. klin. Woch., 1889, p. 560. Levison. Diss. Bonn, 1894. Berl. klin. Woch., 1894, p. 891. Brunton u. Cash. Beitrage zur Physiologic, C. Ludwig gewidmet, 1887, p. 149. Stockmann and Dott. Proc. Roy. Soc. Edinburgh, 1890. British Medical Journal, 1890, ii., p. 189, and 1891, i., p. 157. Engel. Arch. f. exp. Path. u. Pharm., xxvii., p. 419. (Protopine. ) RJieiner. Therap. Monatsch., 1889, p. 393. (Codeine.) Dreser. Ibid., 1898, p. 509. Stursberg. Arch, de Pharmacodyn., iv., p. 325. Winternitz. Pfliiger's Arch., Ixxx., p. 344. Marshall. Med. Chronicle, April, 1901. Riegel. Ztschr. f. klin. Med., xl, p. 347. Holsti. Ibid., xlix., p. 1. Bashford. Arch, internat. de Pharmacodyn., viii., p. 311. Faust. Arch. f. exp. Path. u. Pharm., xliv., p. 217. Cloetta. Ibid., 1., p. 453. Bouma. Ibid., 1., p. 353. (Codeine.) Magnus. Ergebnisse d. Physiol., i., 2, p. 437 (Respiration) ; ii., 2, p. 657 (Intestinal Action). Kaufmann. Ztschr. f. klin. Med., xlviii., p. 260. Minor Drugs of the Opium S'eries. In some other members of the poppy family (Papaveracese), alkaloids are found which bear a close resemblance to those of opium. There are Cheli- donine, -, P-andy-Homochelidonine, Chelerythrine and Sanguinarine ; Protopine is also found in a number of other papaveraceae. These alkaloids are met with in very small quantities in various plants, of which Sanguinaria Cana- densis (Bloodroot) and Chelidonium majus (Celandine) are the best known. Chelidonine and a-homochelidonine resemble morphine in their effects on the central nervous system, but have even less stimulant effect. In the frog no secondary increase in the reflex irritability is produced, but in some mam- mals a slight stimulation of the spinal cord may be caused. They have the 228 ORGANIC DRUGS ACTING AFTER ABSORPTION. same effect as protopine and cryptopine on the muscles and heart, and like them produce insensibility of the skin and cornea when applied locally through paralyzing the terminations of the sensory nerves. The heart is slowed, partly owing to stimulation of the inhibitory centres in the medulla, and partly through direct action on the cardiac muscle. Sanguinarine has very little depressant action, but causes tetanus and wild excitement, so that as far as its action on the central nervous system is con- cerned, it deserves a place between codeine and thebaine of the morphine series. It possesses the same muscular action as protopine, however, and the heart is slowed through direct affection of the muscle. Sanguinarine paralyzes the peripheral sensory endings when applied locally, but this paralysis is preceded by a stage of irritation. It causes violent peristalsis of the bowel, and increases the secretion of saliva. p-homochelidonine resembles protopine and cryptopine closely in its effects, causing the same stimulation of the lower parts of the brain with very slight effects on the intellectual powers, slowing the heart through its muscular action and paralyzing the sensory terminations. Chelerythrine paralyzes the central nervous system without any prelimi- nary increase in the reflex irritability, possesses the muscular action of pro- topine and cryptopine, and first irritates and then paralyzes the sensory terminations. None of these alkaloids have been used in therapeutics, and there would seem to be no indication for them that is not as well met by opium or morphine. None of the plants containing them have been used to any great extent, although Sanguinaria Canadensis was formerly occasionally pre- scribed as a nauseating expectorant and emetic. The " Sanguinarine " of commerce is generally a mixture of the alkaloids with other constituents, and, like the other preparations of the plant, might well be dispensed with. U. S. P. PREPARATIONS. Sanguinaria, the rhizome of Sanguinaria Canadensis, bloodroot, collected in autumn. Tinctura /Sanguinarice, 1-2 c.c. (15-30 mins.). Fluidextractum Sanguinarice, 0.1-0.5 c.c. (2-8 mins.). BIBLIOGRAPHY. H. Meyer. Arch. f. exp. Path. u. Pharm., xxix., p. 397. Schmidt. Arch, der Pharmacie, ccxxxix., p. 393. Anhalonium. A number of alkaloids, some resembling morphine, others strychnine in their effects on animals, have recently been isolated from dif- ferent members of the Anhalonium genus (Fam. Cactacese). In Mexico, and along the southern boundary of the United States, where those plants are indigenous, some of them are used as narcotics in the religious rites of the Indians and are known as Pellote, Peyotl, or Muscale or Mezcal Buttons. The symptoms arise for the most part from the cerebrum and differ from those of opium and cannabis indica in the frequency with which color visions are induced, these consisting in constantly shifting flashes of brilliant colors. Mezcal eating is not followed by merriment as in cannabis nor by sleep like morphine but depression of some functions is indicated by the imperfect co- ordination of the movements, the retarded perception and the errors in the estimation of time. The exaltation seems to be caused for the most part by one of the alkaloids, mezcaline. Very large doses have induced unpleasant symptoms through depression of the respiration. Anhalonium and pellotine, one of its alkaloids, have been used as narcotics in a few cases of insomnia. Lewin. Arch. f. exp. Path. u. Pharm., xxiv., p. 401 ; xxxiv., p. 374. Heffter. Ibid., xxxiv., p. 65 ; xl., p. 385. Mogilewa. Ibid., xlix., p. 137. Prentiss and Morgan. Med. Kecord, 1896, Aug. 22. Dixon, Journ. of Physiol., xxv., p. 69. HYDRASTINE AND HYDRASTININE. 229 iv. TTVDRAsypra AND HYDRASTININE. Another alkaloid which is closely related to those of opium chem- ically and pharmacologically, is Hydrastine, which occurs in the Hydrastis Canadensis (Golden Seal) along with Berberine and Cana- dine. Hydrastine (C 21 H 21 NO 6 ), when exposed to oxidizing agents such as potassium permanganate, is decomposed into opianic acid and Hydrastinine (C n H 13 NO 3 ), another alkaloid. Narcotine (C 22 H 23 NO 7 ), the opium alkaloid, undergoes a simi- lar decomposition into opianic acid and Cotarnine (C 12 H 15 NO 4 ). Hydrastine and narcotine differ only in a hydrogen atom of the former being substituted by OCH 3 in the latter, and a similar relation exists between hydrastinine and cotarnine. All four are derivatives of isoquinoline. The action of hydrastis is similar to that of hydrastine, the berberine and canadine having little effect ; the latter is as poisonous as hydrastine, but is present only in very small quantities in the plant. Action. Hydrastine causes in frogs an increase in the reflex irrita- bility and eventually tetanus exactly resembling that produced, by strychnine, and like it terminating finally in paralysis. Unlike strych- nine, however, it weakens and eventually paralyzes the muscles in the same way as the alkaloids of sanguinaria. The heart is rendered slow and weak, partly by the central stimulation of the inhibitory ap- paratus and partly by direct action on the muscle fibres. In mammals, the pulse is slowed by comparatively small quantities, while somewhat larger doses cause general feebleness, tremor, dyspnoea, and incoordination in the movements. Very large quantities elicit clonic and then tonic convulsions and tetanus, during which the respira- tion ceases. The pulse is slowed at first from stimulation of the vagus centre, is afterwards quickened from its paralysis, and still later be^ comes slow again from direct action on the cardiac muscle. The blood-pressure rises from constriction of the arterioles but after- wards falls, partly from their dilatation and partly from the weakness of the heart ; the_constriction of the arterioles is due to stimulation of the vaso-motor centre in the medulla. Several authors have asserted that" the injection of hydrastine solution is followed by rhythmic con- tractions of the uterus similar to those observed during labor, but this has been denied by others, and cannot be said to have been satisfac- torily established either by experiment or by clinical experience. Another statement which is frequently met, is that hydrastis and hydrastine increase the secretion of the bile, but this is founded upon very imperfect experiments and is in all probability erroneous. Hy- drastine has no local anaesthetic action. Hydrastine then stimulates first the centres of the medulla oblongata, and produces slowing of the pulse, an increased arterial tension and accelerated respiration. Larger quantities stimulate further the spinal cord and eventually paralyze both medulla and cord. In addition to this central action, hydrastine v/eakens and paralyzes muscle, this 230 ORGANIC DRUGS ACTING AFTER ABSORPTION. being confined to the hear t^ in warm-blooded animals, but extending to the ordinary striated muscle of the frog. These effects would appear to give hydrastine a position near that of thebaine, though it differs from most of the opium alkaloids in seeming to act more strongly on the medulla than elsewhere in the central nervous system. Its action on the heart and muscle is analo- gous to that of several of the opium alkaloids. Hydrastine is excreted as such in the urine, and does not form hydrastinine in the organism as might have been surmised from its behavior towards oxidizing sub- stances. When it is administered for some time, a cumulative action is said to be developed. Canadine in small quantities produces depression and drowsiness followed by complete recovery without further symptoms. In larger quantities v. Bunge found that it caused a short stage of excitement, which was followed by depression and paralysis of the central nervous system. It has little or no effects on the mammalian circulation when administered in ordinary doses, but very large quantities cause weakness and arhythmia of the heart. Its injection is followed by violent peristalsis of the intestine and diarrhoea. Can&dine is present in only very small quantity in the Golden Seal and has apparently little importance in therapeutics. Hydrastinine, an artificial alkaloid formed from hydrastine, has of late years attacted a certain amount of attention from its alleged power of arresting hemorrhage. It seems to differ from hydrastine in,caus- ing no marked disturbance of the centres of motion and feeling save in enormous doses, which paralyze the nervous system, "and, in the frog, the terminations of the motor nerves in muscle (Santesson). On the other hand, its action on the medulla oblongata resembles that of the parent substance. The heart is slowed somewhat by small doses, ap- parently from stimulation of the vagus centre, and the arterial tension rises further than after hydrastine. Unlike the latter, however, hy Idrastinine causes a very prolonged augmentation of the blood-pressure because it does not tend to depress the heart to the same extent as hy drastine. In fact, several authors believe that it increases the effi- ciency of the heart movements from action on the muscle, although the pulse may be somewhat slowed by stimulation of the inhibitory centre. After very large quantities, the pulse is often extremely rapid from paralysis of the inhibitory centre. The cause of the increased arterial tension is still undecided. There seems to be undoubted stimulation of the vaso-motor centre, but ac- cording to some writers, the peripheral vessels are contracted by direct action on the walls as well. This statement seems open to question, however, none of the 'experiments on which it is founded being alto- gether satisfactory ; thus, while Falk found well marked contraction of the abdominal, and especially of the renal vessels, v. Bunge denies that the renal vessels are constricted. It has been repeatedly stated that hydrastinine produces rhythmical contraction of the uterus, and even abortion in animals, but this does not seem to be correct. It ap- pears to have no direct action on the muscle of this organ, but its ves- HYDRASTINE AND HYDRASTININE. 231 sels undergo constriction like those of the rest of the body, and this may stop haemorrhage and at the same time cause asphyxia of the foetus and abortion. It must be stated, however, that several writers on hydrastinine hold that it causes contraction of the uterus through action on the muscle, and the question deserves further investigation. Archangelsky states that a 10 per cent, solution of hydrastinine ap- plied locally causes dilatation of the pupil, which reaches its maximum in 2-3 hours, and lasts for 12-15 hours. PREPARATIONS. Hydrastis (IT. S. P.), Hydrastis Rhizoma (B. P.), the rhizome and roots of Hydrastis Canadensis, Golden Seal. Fluldextractum Hydrastis (U. S. P.), 1-4 c.c. (15-60 mins.). Extractum Hydrastis Liquidum (B. P.), 5-15 mins. Glyceritum Hydrastis (U. S. P.), 1-4 c.c. (15-60 mins.). Tinctura Hydrastis (U. S. P., B. P.), 1-4 c.c. (15-60 mins.). Hydrastina (U. S. P.), white bitter crystals almost insoluble in water. Hydrastinince Hydrochloridum (U. S. P.), 0.03-0.1 G. (-2 grs.), given in solution hypoderniically or by the mouth, or in pills or tablets. Therapeutic Uses. Hydrastis has been used as a stomachic bitter and the large quantity of berberine contained in it would seem to give it a place along with the simple bitters. It has also been credited with some obscure action on the mucous membranes when locally applied, through which it is said to benefit many forms of catarrhal inflamma- tion. For this purpose the glycerite may be used. Besides various conditions in which its use was attended by doubtful success, it has been used in haemorrhage from the uterus ; but for this purpose, hydrastinine ought to be preferred, as it causes a much greater con- striction of the peripheral vessels than hydrastine, and acts less on the heart. The conditions in which it is indicated seem to be moder- ate haemorrhage, for which no contraction of the uterine walls is re- quired ; for example, hydrastinine is of value in excessive menstrual flow, while in post-partum hemorrhage it seems to have little effect, because here the haemorrhage is to be met rather by inducing contrac- tion of the uterine walls by the use of ergot than by constricting the vessels, There seems no reason why hydrastinine should not be used in other forms of haemorrhage, for it does not act more on the uterine vessels than on others throughout the body. Hydrastinine has been found to lessen somewhat the irritability of the motor areas of the brain, and its use has, therefore, been suggested in epilepsy. Cotarnine has been introduced under the name of Stypticine as a substitute for hydrastinine in uterine hemorrhage. Dose, 0.02-0.03 G. (|~4 gr.). It resembles hydrastinine in its general action and has received some recom- mendation at the hands of gynecologists. BIBLIOGRAPHY. P. Marfori. Arch. f. exp. Path. u. Pharm., xxvii., p. 161. Arch. Ital. de Biol., xxviii., p. 191. K Folk. Virchow's Arch., cxix., p. 399 ; cxlii., p. 360. 232 ORGANIC DRUGS ACTING AFTER ABSORPTION. Cerna. Therap. Gaz., 1891, pp. 289, 361. K. v. Bunge. Arbeiten a. d. pharmakolog. Institut. Dorpat, xi. and xiL, p. 119. Fellner. Centralbl. f. Physiol., xi., p. 374. Santesson. Skandin. Arch. f. Physiologie, vi., p. 308. Ronsse. Arch, de Pharmacodynam. , iv., p. 207 ; v., p. 21. Philipps and Pembrey. Brit. Med. Jour. 1898, ii., p. 1052. V. OANNABIS INDIOA. The hemp plant possesses no pharmacological interest when grown in temperate regions, but when cultivated in warm climates as in India, Egypt or the southern United States, it develops products which induce marked derangements of the central nervous system. The Indian plant was formerly supposed to be a distinct species, but differs so little from the European form that 'botanists now consider them merely varieties. The old name of Cannabis Indica has, however, been retained in medicine. Its introduction into Western medicine dates only from the beginning of last century, but it has been used as an intoxicant in Asiatic countries and in Africa since unknown time, and under the names of Hashish, Bhany, Ganja, Charas or Churrus, is habitually indulged in by some one or two hundred millions of mankind. Some of the preparations are smoked either alone or mixed with tobacco ; others form an intoxicating drink, while in others it is mixed with sugar or honey and taken as a confection. The active principle of Indian hemp has been found by Wood, Spivey and Easterfield to be a red oil or resin boiling at a high temperature, which they term Cannabinol ; this was found by Marshall to induce the typical effects of cannabis indica in man and animals. Frankel states that cannabinol is a phe- nolaldehyde of the formula OH C 20 H 28 COH. Symptoms. The effects of cannabis indica are chiefly due to the changes in the central nervous system, in which it induces a mixture of depression and stimulation similar to that seen occasionally under morphine. Its action is much less constant, however, and seems to depend very largely on the disposition and intellectual activity of the individual. The preparations used also vary considerably in strength, and the activity of even the crude drug seems to depend very largely on the climate and season in which it is grown, so that great discrep- ancies occur, in the accounts of its effects. Soon after its administra- tion, the patient passes into a dreamy, semiconscious state, in which the judgment seems to be lost, while the imagination is un trammeled by its usual restraints. The dreams assume the vividness of visions, are of boundless extravagance, and, of course, vary with the character and pursuits of the individual. In the eastern races they seem generally to partake of an amorous nature. The true believer sees the gardens of paradise and finds himself surrounded by troops of houris of un- speakable beauty, while the less imaginative European finds himself un- accountably happy and feels constrained to active movement, often of a purposeless and even absurd character. Ideas flash through the mind without apparent continuity, and all measurement of time and space CANNABIS INDICA. 233 is lost. True hallucinations may appear, but are often absent, the chief features of the action being merriment, comfort, well-being and self-satisfaction. Often less pleasant thoughts obtrude themselves, however, such as the fear of impending death or of some imminent in- definite danger. During this period, the consciousness is not entirely lost, for the patient often feels that his dreams are unreal, his satisfaction unfounded and his movements ridiculous, but he cannot restrain them ; he can give a coherent account of his condition when aroused and answer questions intelligently. The sensation of pain is lessened or entirely absent, and the sense of touch is less acute than normally. Later the dreams alternate with periods of complete unconsciousness, from which the patient can be aroused easily, and the symptoms eventually pass into tranquil sleep, from which he awakes refreshed, and, as a rule, without any feeling of depression or nausea. In the majority of cases the preliminary stage of exaltation is very short or entirely absent in Europeans, the first effects of the drug often being heaviness, drowsiness, noises in the ears and numbness of the extrem- ities, which pass into deep sleep. According to Dixon the drug is much more exhilarating when inhaled than when swallowed, and this may account for some of the variations in its action. In some cases, acute mania and convulsive attacks have been developed, and among the natives of India catalepsy occasionally occurs. In animals, the effects of cannabis indica seem to resemble those in man and present the same marked variations ; a stage of exaltation with increased movement is sometimes present and is followed by depres- sion, lassitude and sleep. The reflex excitability is first increased and then diminished in frogs. Vomiting is often induced in dogs and cats, but cannabis indica differs from opium in producing no disturbance of the digestion and no constipation. The heart is generally accelerated in man, when the drug is inhaled ; the intravenous injection in animals slows the pulse partly through inhibitory stimulation and partly through direct action on the heart muscle. This action on the heart is stated by Dixon to be the cause of death after poisonous quantities, for he found the respiration persist for some seconds after standstill of the heart. The pupil is generally somewhat dilated. Polyuria is stated to occur in dogs in which cannabinol appears to be excreted by the kidneys in combination with glycuronic acid (Frankel). Death from acute poisoning is extremely rare, and recovery has oc- curred after enormous doses. The continued abuse of hashish in the East sometimes leads to mania and dementia, but does not cause the same disturbance of nutrition as opium, and the habitual use of small quantities, which is almost universal in some Eastern peoples, does not seem .detrimental to them, although among Europeans it might possibly be as fatal as that of morphine. Some tolerance is rapidly acquired. 234 ORGANIC DRUGS ACTING AFTER ABSORPTION. PKEPAKATIONS. Gannabis Indica (U. S. P., B. P. ), Indian hemp, the flowering tops of the female plant of Cannabis sativa (hemp), grown in the East Indies. Extractum Cannabis Indices (U. S. P., B. P.), 0.02-0.06 G. (i-1 gr.). Fluidextractum Cannabis Indicce (U. S. P.), 0.1-0.3 c.c. (2-5 mins.). TINCTURA CANNABIS INDICLE (U. S. P., B. P.), 1-2 c.c. (15-30 mins.). The preparations vary extremely in strength and many are entirely inert, especially when they have been kept some time. The unofficial prepara- tions, such as u cannabin tannate, " cannabinon, etc., seem to be no more reliable than the pharmacopceial ones, and offer no advantages at all com- mensurate with their price. Therapeutic Uses. Cannabis indica is used as a hypnotic in cases of sleeplessness from nervous exhaustion and, less often, from pain. It is not nearly so reliable as opium, and in fact produces sleep in only about 50 per cent, of the cases, according to some authors. On the other hand, it does not disturb the digestion and produces no subsequent nausea and depression, and may therefore be employed in some cases in which opium is contraindicated. It is of use in some cases of migraine, and has been prescribed as a substitute for opium in mental diseases. Lactucarium (U. S. P.), the dried juice of Lactuca virosa, the common lettuce, is reputed to have some hypnotic properties. It contains neutral bitter substances, lactucin and lactucon, and it has been stated recently that traces of hyoscyamine and atropine are also present. In any case its action is so feeble that half an ounce has been administered to a dog without effect, and it seems quite unnecessary to include it in the pharmacopoeia. U. S. P. Tinctura Lactucarii. Syrupus Lactucarii. BIBLIOGRAPHY OF CANNABIS INDICA. Hare. Therapeutic Gazette, 1887, p. 225. Wood. Proc. Amer. Phil. Soc., 1869, p. 226. Zuco u. Vignolo. Arch. Ital.de Biol., xxiii., p. 409. Bericht. der Berl. Chem. Ge- sellsch., 1895, iv., p. 558. Marshall. Lancet, 1897, i., p. 235. American Medical Journal, 1898, ii., p. 882. Dixoji. Brit. Med. Journ., 1899, ii., p. 136. Frankel. Arch. f. exp. Path. u. Pharm., xlix., p. 266. VI. APOMORPHINE. When morphine is acted on by acids and by some other dehydrat- ing agents, it loses a molecule of water, and a new alkaloid is formed, Apomorphine (C 17 H 17 NO 2 ). Through this change the action of the original alkaloid is consider- ably modified ; apomorphine preserves the stimulant, but loses to a great degree the depressant action of morphine on the central nervous system. This stimulant action extends over the whole central nervous system in animals, but is most developed in the " vomiting centre " of the medulla oblongata. Symptoms. In man, apomorphine in doses of 5-10 mg. (^-J gr.) APOMOEPHINE. 235 induces within 10-15 minutes nausea and vomiting, accompanied by the usual attendant phenomena, but with no symptoms which cannot be directly included in these. Very often the nausea passes off imme- diately after the evacuation of the stomach, but when larger quantities have been administered, repeated vomiting and retching may occur. Occasionally depression and sleep follow the emesis after even small doses. FlG - 19 - The attendant symptoms are profuse saliva- tion, increased secretion of the mucous glands of the nose, throat and bronchial passages, tears and a cold perspiration. A feeling of depression and muscular weakness and accel- eration of the pulse are also well-known symptoms accompanying nausea and vomit- ing, and are present after apomorphine. These are all to be regarded as sequelae of the emetic action, however, and not as due to the direct action of the drug on the glands and other organs. In a few instances the depression and weakness have passed into alarming collapse, but no actual fatality is recorded from the use of apomorphine. Very small doses of apomorphine may induce the secondary symptoms without actual vomiting. Thus the saliva, perspiration, tears and other secretions may be augmented by quantities which are too small to act as emetics, though there is no question that these are due to the commencing emetic action apomorphine. The volume in- . . ,. . spired in each 2% mins. is meas- 111 dogS and Cats, Small quantities ellClt ured along the perpendicular, the . , w , iii i time aloug the horizontal line. the same effects as in man, but larger doses At first about GOO c.c. represents 600- : are followed by symptoms of general nervous stimulation. In the herbivora, which are incapable of vomiting, these symptoms follow the injection of comparatively small quantities and are much more marked. The rabbit, for example, becomes restless and easily alarmed ; it moves about, climbs up the walls of its cage and gnaws anything it can reach. Circus movements are developed very often, especially in the dog, the animal running unceasingly in a circle and striking against obstacles in its path, apparently unconscious of all its surroundings and overcome by the impulse to continual movement. The respiration is very much accelerated (Fig. 19). After very large quantities the movements become less coordinated, and eventually tetanic convul- sions set in, during which the respiration ceases, while the heart con- tinues to beat for some time afterward. Apomorphine induces vomiting through changes in the medulla ob- 236 ORGANIC DRUGS ACTING AFTER ABSORPTION. longata and not by irritation of the stomach. This is shown by the fact that it acts much more quickly and in smaller doses, when it is injected hypodermically than when it is swallowed, and also by the fact that if the medulla be brushed with apomorphine solution, vomiting follows immediately. . It is even disputed whether apomorphine has any effect on the gastric movements at all, for Batelli states that the stomach remains quite passive during vomiting, while Schiitz found it undergoing antiperistaltic movements towards the cardiac orifice. In any case the movements of the stomach play an unimportant part in the evacuation of its contents by apomorphine, and all the phenomena in man are to be ascribed to medullary action. Apomorphine is said to have some anaesthetic effects on the cornea when a solution is dropped upon it. It causes cloudiness and conse- quent dimness of sight, however, and has not been used practically for this purpose. Apomorphine is not excreted into the stomach like morphine, nor has it been found in the mucous membranes of the air passages, and it is possible that it is decomposed in the tissues. The symptoms induced by apomorphine resemble in some degree those following morphine in many animals, for here too the first symp- tom is vomiting accompanied by signs of excitement, which are, how- ever, generally attended by those of depression of some parts of the central nervous system. The similarity between the effects of apomor- phine and of morphine on the cat, for example, is particularly striking. In man, however, the effects are very different, for apomorphine seems to have lost all the depressant action of the parent body, although here again it must be remembered that morphine occasionally causes vomit- ing, so that apomorphine does not depart so far from the type of the opium alkaloids as would at first sight appear. In the frog, apomorphine causes a transient stimulation of the central nervous system, followed by depression and paralysis. Larger quantities weaken and paralyze the muscles and the heart through direct action on the fibres. The muscular action may also be demonstrated on excised muscles, in which the elasticity is lessened, and the contractions become weaker and eventually cease entirely. This weakening in the contraction of the muscles has not been observed in mammals, and is quite distinct from the feeling of weakness accom- panying nausea in man, for the latter is certainly of cerebral origin. No emesis is induced in frogs, although these animals are not, like the herbivora, incapable of vomiting. Apocodeine is formed from codeine in the same way as apomorphine from morphine, but it differs entirely from apomorphine in its action and resembles nicotine in paralyzing the sympathetic ganglia. It causes purgation when injected hypodermically, apparently from removing the normal inhibition of the bowel movements (Dixon). If codeine be heated with hydrochloric acid (B. P.), apomorphine is formed, and not apocodeine. PREPARATIONS. APOMOKPHINJE HYDROCHLORIDUM (U. S. P., B. P.), 3-6 mg. (^VrV gr.). INJECTIO APOMOEPHIN^E HYPODERMICA (B. P.), 1 per cent., 5-10 mins. APOMORPHINE. 237 Apomorphine hydrochlorate is a grayish-white crystalline substance, very soluble in water and turning dark green or even black, especially when kept long in solution. This change in color does not appear to impair its activity appreciably. The doses given above are those for hypodermic use to induce vomiting. The same quantity may be given by the mouth as an expectorant. Therapeutic Uses. Apomorphine is used chiefly as an emetic, and for some purposes presents several advantages over the older drugs employed with this object, inasmuch as it acts more promptly and can be administered by the hypodermic needle, while the other emetics have to be given by the mouth, which is a serious drawback in cases of poisoning. The more important of these older drugs are ipecacu- anha, tartar emetic (antimony), ammonium carbonate, the sulphates of copper and zinc and alum. Vomiting is not now such an important method of treatment as it was formerly, and the emetics are less frequently employed to evacuate the stomach than other less heroic measures such as the passage of the stomach tube. Emesis may be indicated in poisoning, and here apo- morphine is especially useful. But in the great majority of cases a better method of treatment is repeated washing of the stomach by means of the stomach tube, for in narcotic poisoning apomorphine not infrequently fails to act owing to the depression of the vomiting centre, and in corrosive poisoning a certain amount of danger attends its use, as the pressure on the walls of the stomach exerted by the contraction of the diaphragm and abdominal muscles may lead to the rupture of the weakened walls of the organ. In irritant poisoning, on the other hand, the reflex vomiting set up is generally sufficient to empty the stomach, and the indications are rather to allay the gastric irritation than to increase it by causing violent movements of the abdominal walls by apomorphine. Emetics, such as apomorphine, have been used occasionally to cause pressure on other abdominal organs, e. H 5 J-NCH > H HN CO NH CO Theophylline. Caffeine. v CH S N-C-N \ > CH oi |- NCH > CH CH 3 N CO Action. These all resemble each other in most points of their pharmacological action, although caffeine acts on the central nervous system as well as on the kidneys, muscle and heart, while theobromine has comparatively little effect except on the last three. Central Nervous System. In mammals the injection of large quan- tities of caffeine is followed by symptoms closely resembling those in- duced by strychnine. The reflex irritability is remarkably increased, the lightest touch being followed by powerful contraction of almost all the muscles of the body. After a time these contractions occur with- out any apparent stimulus, and culminate in tonic convulsions which last for several seconds. During these the respiration ceases from the respiratory muscles being involved in the spasm and occasionally it fails to be reinstated when the convulsions pass off. In other instances the spasms become weaker and occur at longer intervals ; the respira- tion diminishes in frequency and depth and eventually ceases. In man, smaller quantities of caffeine stimulate the central nervous system, in particular that part associated with the psychical functions. The ideas become clearer, thought flows more easily and rapidly, and fatigue and drowsiness disappear. Not infrequently, however, con- nected thought is rendered more difficult, for impressions follow each other so rapidly that the attention is distracted, and it requires more and more effort to limit it to a single object. If the quantity ingested is small, however, the results are of distinct benefit in intellectual work. The capacity for physical exertion is also augmented, as has been dem- onstrated repeatedly by soldiers on the march, and more recently by more exact experiments with the ergograph. The stimulation of the higher nervous centres is often evidenced by the insomnia and restless- ness which in many people follow indulgence in coffee or tea late at night. Kraepelin has investigated the effects of caffeine from the psy- chological point of view, and. finds that both tea and coffee facilitate the reception of sensory impressions and also the association of ideas, especially in fatigue, while the transformation of intellectual concep- tions into actual movements is retarded. This he regards as due to stimulation of the highest or controlling functions of the brain, caffeine 246 ORGANIC DRUGS ACTING AFTER ABSORPTION. acting on the same parts as are first affected by alcohol and the methane derivatives, but altering them in the opposite direction. The effects of caffeine on the acuteness of the senses has been demonstrated by the greater accuracy of touch under its influence. Large quantities of caffeine often cause headache and some confu- sion, and in rare cases of special susceptibility a mild form of delirium may be elicited, or noises in the ears and flashes of light may indicate derangement of the special senses. The pulse is quickened, and oc- casionally palpitation and uneasiness in the region of the heart are complained of. Convulsive movements of the muscles of the hand and tremor in different parts of the body have also been recorded in some cases. These effects are induced only with difficulty in habitual drinkers of tea or coffee, so that the continued administration of small quantities of caffeine evidently gives rise to tolerance. The symptoms induced by caffeine in the lower mammals are due for the most part to its acting on the spinal cord in the same way as strychnine, though small doses may act on the brain, for they often elicit restlessness and timidity without any marked change in the reflex excitability. The centres in the medulla oblongata are also involved in the effects, as is indicated by a rise in the blood-pressure from stim- ulation of the vaso-motor centre, acceleration of the breathing, and oc- casionally some slowness of the pulse from action on the respiratory and pneumogastric centres. The intracranial bloodvessels are said to be dilated. Frogs show no nervous symptoms that cannot be ascribed to action on the spinal cord, and in some species these are elicited with con- siderable difficulty owing to the muscular action described below. On comparing the effects of caffeine and strychnine on the central nervous system it will be found that while there is a general similarity in their action, the latter causes more marked stimulation of the lower divisions and has less action on the cerebrum in mammals and man. They both produce a general increase in the activity of nerve cells, but caffeine acts more on the psychical, strychnine more on the vital and reflex functions. Theophylline resembles caffeine in its action on the central nervous system, while theobromine induces few or no symptoms of stimula- tion. The monomethyl-xanthines and xanthine itself stimulate the central nervous system in the frog (Schmiedeberg). The Muscular action of caffeine is best seen in the Rana temporaria (grass frog), although it is also induced in other species of frogs, and some rigidity may be elicited in mammals by very large doses. When a few drops of caffeine are injected into the leg of a frog there follows a peculiar stiffness and hardness in the muscles around the point of in- jection, which slowly spreads to other parts of the body and induces the appearance of rigor mortis. The same effect is observed when teased muscle fibres are subjected to a caffeine solution under a high- power microscope. The fibres contract, become white and opaque, and CAFFEINE. 247 look stiff and inflexible ; the transverse striae disappear, while the lon- gitudinal become more easily visible (Fig. 21). This appearance is due to the death and rigor mortis of the fibres. Fiirth FIG. 21. states that the myogen of muscle is formed into myo- genfibrin and coagulated by I the addition of caffeine to its ( solutions outside the body, so m that the rigor induced by caffeine seems due to a com- Bjjj paratively simple reaction ii between the poison and the proteids of the muscle fibre. In Small quantities Caffeine A muscular fibre of the frog (highly magnified). A, intfaacAa V, iwi+okili'tir ^f normal 5 B > after the application of caffeine solution. The increases the irritability OI coa rse stri* in B are the folds of the sarcolemma. muscle as well as its absolute strength and extensibility, that is, the muscle contracts on a weaker stimulus and against a greater load than it does normally. The amount of work done before fatigue sets in is also increased, unless when large quantities are applied, when the capacity for work is less- ened ; and with the first appearance of rigor it ceases to react to stimuli altogether. Sobieranski has recently shown that in ordinary doses caffeine increases the work done by the human muscles when they are stimulated by electric shocks. The universally recognized effect of tea and coffee in increasing the capability for physical work and in relieving fatigue has generally been regarded as due to changes in the nerve cells, but according to Kraepelin and others is really of peripheral origin and explained by the direct action on the muscle. While the action of theobromine on the central nervous system is much less marked than that of caffeine, muscle enters into rigor after the former more readily and xanthine exceeds even theobromine in its power to produce this change. The action of caffeine on the Circulation is exerted in two directions, on the vaso-motor centre in the medulla and on the heart itself. Along with the rest of the central nervous system, the vaso-motor area un- dergoes stimulation and the smaller arteries are therefore contracted, causing a marked rise in the arterial pressure. In the frog's heart caffeine in very small quantities is found to in- crease the absolute strength, that is, the heart contracts against a greater aortic pressure than it would normally, and at the same time the amount of blood expelled by each beat is slightly increased. The rhythm is generally somewhat accelerated by small doses, but this ef- fect is often of very short duration. On the absorption of larger quantities, the heart first becomes slower and its volume smaller, then the apex ceases to relax with the rest of the ventricle and remains white and contracted, and eventually the whole heart passes 248 ORGANIC DRUGS ACTING AFTER ABSORPTION. into a condition of rigor exactly resembling that seen in the skeletal muscles. When moderate quantities of caffeine are injected intravenously in mammals, the heart is accelerated, without any marked change in the extent of systole or diastole. The increased rate is independent of any action ou the regulatory mechanism of the heart, for it is seen in hearts in which the accelerans has been cut and the inhibitory apparatus paralyzed by atropine. It is probably due to direct action on the heart muscle for, as has been stated, an analogous increase in irrita- FIG. 22. Tracing of the ventricle of the dog's heart : A, normal ; B, after caffeine. The lever moves upwards during systole, downwards during diastole. The only alteration caused by caffeine is acceleration. The slightly larger excursion in diastole in B is mechanical. (Contrast tracings under digitalis.) bility occurs in voluntary muscle. The increased irritability of the cardiac fibres also accounts for the fact that stimulation of the vagus is followed by less slowing of the heart after caffeine than before its administration. In man the heart rhythm is often found slower after caffeine, and this appears to be due to stimulation of the inhibitory centre in the medulla oblongata, the increased inhibition proving more than sufficient to counterbalance the acceleration which would arise from the direct action of the caffeine on the heart muscle. After large quantities of caffeine the heart becomes weak and irregular and after death it is found in diastole. The increased rate of the heart beat is not always accompanied by an increase in the amount of blood expelled in a unit of time (Bock), although this is often the case. Apparently the contractions of the ventricle follow each other so rapidly that the time is often insufficient for the inflow of the usual amount of blood. The increase in the blood-pressure under caffeine is therefore tojbe ascribed for the most part to the action on the vaso-motor centre,, al- though not infrequently this is supplemented by an increased efficiency of the heart. Theobromine and xanthine possessing but little action in CAFFEINE. 249 the vaso-motor centre, scarcely raise the blood-pressure although they have the same effect on the heart as caffeine. Theobromine causes some dilatation of the coronary arteries when it is perfused through ., the heart, while caffeine is devoid of this action. The Respiration is quickened and strengthened by caffeine, owing to a stimulant action on the medullary centre. This effect on the respira- tion is seen in the improvement of the respiration in cases of dangerous poisoning with alcohol, opium and other drugs which prove fatal by failure of the respiration, but is much less marked in normal animals. The Temperature has been found to be raised by caffeine through its action on the nervous centres and perhaps on the muscles. The in- crease is, however, comparatively insignificant (0.5-1 C.) and is seen only in cases in which an almost poisonous dose has been used. The Alimentary Tract is not affected by caffeine, but after theobro- mine discomfort and loss of appetite are sometimes complained of, probably owing to changes in the gastric mucous membrane. These are much more marked after even small doses of theophylline, and small haemorrhages and erosions have been found in the stomach, both in man and animals (Allard). Kidney. The most important property of caffeine from a thera- peutic point of view is its power of increasing the secretion of urine. It is an everyday experience that strong coffee or tea increases the urine to a much greater extent than the same amount of water, and this has been shown to be due to the caffeine contained in these bev- erages. It is still disputed how caffeine causes diuresis, for while the most generally accepted view is that of Schroeder, that caffeine acts directly on the renal cells, some investigators hold that the increased urinary secretion is due to local changes in the renal circulation. As a general rule the vessels are dilated and the kidney volume is enlarged during caffeine diuresis, but this may be merely an accompaniment and not the cause of the increased activity. In any case the diuresis is due to changes within the organ and is quite independent of the action of the drug in other parts of the body. These may in fact counteract the real action and prevent the diuresis, through stimula- tion of the vaso-constrictor centre, which retards the circulation in the kidney and lessens the amount of fluid reaching the renal cells (Schroe- der). This inhibitory action of the vaso-motor centre may be elimi- nated by such medullary depressants as chloral, under which the caf- feine diuresis may be elicited with much greater certainty. Theobro- mine has a more constant effect on the kidney and causes even greater activity in that organ than caffeine, and this was explained by Schroeder as being due to its having little or no stimulant effect on the vaso-constrictor centre. Theophylline appears to increase the urine more than any other of ( the group, with the possible exception of paraxanthine. In the caffeine diuresis, the fluid part of the urine is increased chiefly, but the solids also undergo an augmentation, though not to the same extent. Among the solids the chief increase is seen in the 250 ORGANIC DRUGS ACTING AFTER ABSORPTION. FIG. 23. sodium chloride, the nitrogenous constituents undergoing less alteration although they also rise in amount ; a small amount of sugar is often found in the urine, more especially if the food has contained large quantities of sugar- forming substances, but this glycosuria is probably due merely to the large quan- tities of fluid sweeping some of the sugar of the blood along with it, and does not indicate any dangerous alteration in the renal epithelium or in the metab- olism. The excretion of large quantities of fluid in the urine is, of course, accom- panied by a diminution of the fluids of the blood, but the latter soon recuperates itself from the tissues. If there is any accumulation of liquid, such as oedema, it is drained into the blood to replace the fluid thrown out by the kidney, and caf- feine may accordingly be used to remove cedema or dropsy iu this way. If no such accumulation exists, the blood draws on the fluids of the intestine and stomach, and their withdrawal leads to the sensa- tion of thirst. As a diuretic, caffeine is distinctly inferior to theobromine ; in the first place because the diuresis is less certain and is often accompanied by ner- vous symptoms sleeplessness and rest- lessness ; and secondly because the in- crease in the secretion is smaller and lasts for a shorter time. Excretion. Caffeine is excreted in the urine to a very small extent as such. During its passage through the body it loses its methyl groups and first becomes dimethyl- and then monomethylxanthine. Eventually xanthine is formed and this probably breaks up into urea. In the urine are found small quantities of the unchanged drug, accompanied by larger quantities of dimethylxanthine and mono- methylxanthine. After theobromine and theophylline some of the unchanged drug is found in the urine along with monomethylxanthine. The exact order in which the methyl groups are lost in the tissues ap- pears to differ in different animals ; in the dog all three isomeric di- methylxanthines are formed from caffeine and after large doses appear in Caffeine diuresis in a rabbit. The amount of urine passed in ten minutes is represented by the height of the rec- tangles. The first of these, A-B, repre- sent the normal secretion. At B a small dose, and at C a large dose of caffeine was injected intravenously, and the secretion is accordingly increased. The shaded part of the rectangles represents the amount of solids in the urine. It will be noted that these are increased but not to the same extent as the fluid. The dotted line represents the average height of the blood-pressure during each period often minutes. The animal had received a large dose of chloral to de- press the vaso-motor centre and the heart, and caffeine had, therefore, little or no effect on the height of the blood- pressure. CAFFEINE. 251 the urine, although theophylline predominates, while in the rabbit and in man paraxanthine is formed in larger amounts. The monomethylxanthines are also excreted in different proportions in different animals, heteroxanthine prevailing in man and the rabbit. PREPARATIONS. CAFPEINA (U. S. P., B. P.), long, white, silky crystals, without odor, but possessing a bitter taste, but little soluble in cold water, more so in alcohol, still more so in boiling water. 0.05-0.3 G. (1-5 grs.). CAFFEINA CITRATA (U. S. P.), CAFFEINE CITRAS (B. P.), a white powder, consisting of a weak chemical combination of citric acid and caffeine. It is decomposed by mixture with more than 3 parts of water. 0.1-0.5 G. (2-8 grs.). CAFFEINA CITRATA EFFERVESCENS (U. S. P.), CAFFEINE CITRAS EFFER- VESCENS (B. P.), a mixture of citrated caffeine with sodium bicarbonate, tar- taric acid and sugar. On throwing the powder in water it effervesces, owing to the acids acting on the bicarbonate and liberating carbonic acid. This preparation is an extremely weak one, containing only 1 per cent, of caffeine in the U. S. P. and about 2 per cent, in the B. P. Caffeine is best prescribed either in powder or in tablets formed from either of the first two preparations. It may also be given in water with salicylate of soda, which aids its solution. THEOBROMINA (unofficial) is a crystalline powder even less soluble than caffeine, and is absorbed with difficulty when given alone. It is generally prescribed in doses of 0.5 G. (8 grs.) three times a day, but larger quantities may be given. Solutions of salicylate of soda dissolve it much more readily than pure water. DITJRETINE and Agurine are double salts of sodium-theobromine with the salicylate and acetate of sodium respectively and are much more soluble than theobromine. The dose is 0. 5-1 G. three times a day, either in powder form or in solution. Theocine, an artificial theophylline, is a white crystalline powder, slightly sol- uble in water. Dose, 0.2-0.3 G. (3-5 grs.) in powder or tablets. Guarana (U. S. P.), a brown paste derived from the seeds of Paullinia sor- bilis and containing caffeine and theobromine along with some tannic acid. Fluidextractum Guarance (U. S. P.), 3-8 c.c. Numerous preparations of Kola nut are now put on the market, but the pure principles are preferable. Therapeutic Uses. The action of caffeine on the central nervous system has led to its employment in a number of different conditions. Thus, in nervous exhaustion it may be used to stimulate the brain, and in collapse its action on the vaso-motor and respiratory centres has been found of value the blood-pressure rises, the whole tone of the circu- lation is improved and the respiration becomes quicker and less shallow. In narcotic poisoning with failing respiration, caffeine may be used to stimulate the centre in place of strychnine or atropine; in opium poisoning more particularly, strong coffee has long been used, but caffeine might be substituted with advantage. Its stimulant action on the brain, and more especially on the respiration, renders it an antidote in dangerous cases of alcoholic poisoning also. Some forms of migraine and headache are relieved by caffeine, but in others it seems rather to intensify the pain ; this action has been attributed to its dilating the cerebral vessels. Kola preparations are often advised as general tonics in weakness and neurasthenia. 252 ORGANIC DRUGS ACTING AFTER ABSORPTION. Caffeine has been used largely for its action on the heart and is often said to be a substitute for digitalis, though as a matter of fact, it can- not replace the latter, the action of the two on the heart being entirely dissimilar. In cases of heart weakness without marked dilatation and incompetency of the valves, it may be of service as it increases the activity of the ventricle, but its reputation in cases of cardiac disease is due mainly to the removal of dropsy through its diuretic action. The contraction of the arterioles following the use of caffeine may also be of service in feeble action of the heart. In their action on the kidney the members of the caffeine series stand preeminent, no other drug producing such a copious flow of urine as either caffeine or theobromine. As has been explained already, the latter is to be preferred to caffeine as a diuretic, and may be used in all cases in which there is a pathological accumulation of fluid in the body, whether of cardiac, hepatic or renal origin. The results are most brilliant, however, in cases of cardiac dropsy, and here it may be prescribed along with one of the digitalis series. It must be em- phasized, however, that in these cases it cannot supplant digitalis, but merely aids in the removal of the fluid which is obstructing the circu- lation by its pressure, while digitalis relieves the dilatation of the heart. In cases of hepatic dropsy, caffeine and theobromine have also proved of service, although here the treatment can only be considered palliative. In renal dropsy theobromine has been used with somewhat variable results ; it does not seem to increase the albumin in the urine, but not infrequently little or no diuresis follows its administration. This is only to be expected where the renal cells are in such a condition as to be incapable of stimulation. Where the disease is less developed the members of this series produce the usual increase in the se- cretion. Inflammatory effusions do not seem to be lessened to any marked extent by either caffeine or theobromine. Theobromine in very large doses has been found to produce nausea and loss of appetite when taken for long, but in ordinary quantities it produces no symptoms save diuresis. Theocine has undoubtedly greater diuretic power than either caffeine or theobromine, and has been largely advertised for the treatment of dropsy. In a large proportion of cases it causes marked disturbance of the digestive organs, however, and in several instances epileptiform convulsions have followed its use. A large number of other xanthine derivatives have been formed and examined experimentally, but none of them possesses any therapeutic importance (Ach, Schmiedeberg). Coffee and Tea. Coffee is not used in medicine, but in view of its immense dietetic importance it may be mentioned here in what respects it differs from the pure caffeine. The coffee bean contains about f per cent, caffeine, and the roasting does not seem to reduce the percentage at all, as was formerly supposed, and since almost all the caffeine is extracted by the ordinary culinary preparation, a cup of coffee contains from 0.1-0.2 G. CAFFEINE. 253 (1J-3 grs.) of caffeine. Along with the caffeine there are extracted a number of other substances, the most important of which are volatile substances, such as furfuralcohol, produced by the roasting, which have been called Coffeon and resemble in their action the volatile oils. Tea contains a larger percentage of caffeine (about 1J-2 per cent.), but as less tea is used than coffee, each cup may be considered to con- tain 0.1-0.2 G. (1J-3 grs.). In green tea there is a considerable quantity of a volatile oil which also passes into the infusion, but this is not present in black tea, owing to the greater heat used in its manu- facture. Both black and green tea contain about 7 per cent, of tannic acid, but this is only extracted slowly. The bitter taste in tea that has been prepared too long is due to the tannic acid passing into solu- tion. The wakeftilness and the relief from fatigue which are produced by tea and coffee are undoubtedly due to the caffeine contained in them, and are to be ascribed to the central action chiefly, although its action on the muscles may also be of some value here. On the other hand, the feeling of well-being and comfort produced by coffee after a full meal is probably to be explained by the local action of the volatile oil in the stomach. The same result is produced by prepara- tions of the other volatile oils, and, in fact, these are often added to coffee in the form of brandy and other liqueurs. Apart from this local action the volatile parts of tea and coffee (theon, coffeon) seem to have no effect whatever on the economy. In experiments on the activity of the digestive ferments outside the body, it is found that caffeine increases slightly the rapidity of the process, but that coffee and tea retard it considerably. On the other hand, coffee, probably owing to its volatile oils, increases the peristaltic movements of the intestine while caffeine has no effect on them. Tea that contains much tannic acid precipitates the peptones and albumins of the stomach, and may lead to chronic dyspepsia and constipation. It was formerly stated that coffee lessened the tissue change and that it ought therefore to be included among foods, and one enthusiast even suggested that a diet of tea and coffee exclusively should be served out in the besieged fortresses of France in 1870. It has been shown conclusively, however, that far from lessening the metab- olism of the body, coffee and tea increase it, the amount of urea and carbonic acid excreted being considerably augmented by their use. This is only to be expected from the increased activity of the nervous centres, which leads to increased movement and increased consump- tion. Chocolate contains theobromine (0.51 per cent.), instead of caf- feine, and besides this a large amount of fat (cacao-butter 3050 per cent.), starch and albumins. The theobromine does not possess the stimulant action of caffeine on the nervous system, and chocolate may therefore be taken where coffee or tea produces wakefulness. The starch and fat are assimilated by the tissues so that chocolate is a true food. At the same time the cacao-butter is not easily absorbed from 254 ORGANIC DRUGS ACTING AFTER ABSORPTION. the stomach, and may give rise to heaviness and discomfort, and even to indigestion. Chocolate is, therefore, often used freed from the oil, but theobromine is also somewhat detrimental to the gastric mucous membrane after continued use. BIBLIOGRAPHY. Johannsen. Ueber die Wirkungen des Koffeins, Inaug. Diss., Dorpat, 1869. Schmiedeberg. Arch. f. exp. Path., ii., p. 62. Ber. deutsch. Chem. Gesellsch., xxxiv., p. 2550. Archangelsky. Arch, internal, de Pharmacodyn., vii., p. 405. Bock. Arch. f. exp. Path., xliii., p. 317. Filehne. Arch. f. Anat. und Phys., 1886, p. 72. v. Schroeder. Arch. f. exp. Path., xxii., p. 39 ; xxiv., p. 85. Alhanese. Ibid., xxxv., p. 449 ; xliii., p. 305. Bericht. d. deutsch. Chem. Gesell., 1899, p. 2280. Bondzynskiu. Gottlieb. Arch. f. exp. Path. u. Pharm., xxxvi., p. 45 ; xxxvii., p. 385. Heerlein. Pfl tiger's Arch., Hi., p. 165. Dreser. Arch. f. exp. Path. u. Pharm., xxiv., p. 221. Pfliiger's Arch., cii., p. 1. Sobieranski and Modrakowski. Pfliiger's Arch., xcviii., pp. 135, 217. Kraepelin. Ueber die Beeinflussung einfacher psychischer Vorgiinge durch einige Arzneimittel (Jena, 1892) and Psychologische Arbeiten, i., p. 378 ; iii., p. 203. Hellin u. Spiro. Arch. f. exp. Path. u. Pharm., xxxviii., p. 368. Brunton and Cash. Journ. of Phys., ix., p. 112. Lehmann and pupils. Arch. f. Hygiene, xxxii., pp. 310, 327 ; xliv., p. 203. Erdmann. Arch. f. exp. Path. u. Pharm., xlviii., p. 233. Miegel. Congress f. inn. Med., 1884, p. 292. Pawinsky. Ztschr. f. klin. Med., xxiii., p. 440; xxiv., p. 315. Fischer. Ber. d. deutsch. chem. Gesell., xxx., p. 549. v. Ftirth. Arch. f. exp. Path. u. Pharm., xxxvii., p. 389. Kriiger. Bericht. d. deutsch. chem. Gesell., 1899, pp. 2818, 2677, 3336. Arch. f. exp. Path. u. Pharm., xlv., p. 259. Ztschr. f. phys. Chem.,xxi., p. 169; xxxvi., p. 1. Ach. Arch. f. exp. Path. u. Pharm., xliv., p. 319. Katsuyama. Ztschr. f. phys. Chem., xxxii., p. 235. Cushny and Van Naten. Arch, internat. de Pharmacodynamie, ix., p. 169. Anten. Ibid., viii., p. 455. Santesson. Skandin. Arch. f. Physiol., xii., p. 259. Allard. Deutsch. Arch. f. klin. Med., Ixxx. (Theocine.) Impens. Arch, internat. de Pharmacodyn., x., p. 463. (Methylanthine.) IX. CURARA. Curara, woorara, urari or woorali, is an arrow poison used by the natives of South America, who prepare it by extracting various barks and plants. The plants used seem to vary somewhat in different local- ities, but those which produce the symptoms known as curara action are undoubtedly members of the genus Strychnos, such as S. toxifera. Different preparations of curara were found by Boehm to contain different alka- loids. That formerly obtainable owed its activity to Curarine, but the curara now exported contains Tubocurarine, which resembles curarine in its action, and Curine, a weaker poison, which has an entirely different effect. Another prepa- ration examined by him contained three alkaloids, Protocurine, Protocuridine and Protocurarine, the last of which is the most powerful of all the curara alkaloids. Most of the experiments on which the statements regarding curara action are based were performed with the crude drug, but the alkaloids seem to have a very similar effect, with the exception of curine. Action. The chief effect of curara is paralysis of the Terminations of the Nerves Supplying Striated Muscle, and it therefore causes general paralysis of all the voluntary movements. In the mammal the mus- CUEAEA. 255 cles give way one after the other until the animal lies helpless on the ground. It can still move its limbs, but cannot recover its ordinary position, and soon the limbs become totally paralyzed and the respiratory movements alone persist, although they too are slow, weak and jerky. Eventually the respiration ceases also and asphyxia follows, but is not betrayed by the usual convulsions, owing to the paralysis of the motor nerve ends. The blood, however, becomes venous, and the heart soon fails from the asphyxia and not through the direct action of the poison. In the frog similar symptoms are seen, but here the arrest of the respiration is not necessarily fatal, as the skin carries on the exchange of gases, and recovery not infrequently occurs after two or even five days of complete paralysis. The cause of the curara paralysis was dem- onstrated by the classical researches of Claude Bernard and Kolliker. If the sciatic nerve of the frog be stimulated during the paralysis no movement follows, but if the artery of one leg be ligatured before the application of the poison this limb remains unparalyzed and reacts to reflex irritation, while the rest of the body is perfectly motionless. These facts can only be interpreted in one way ; the paralysis is peri- pheral and not central, and may, therefore, be due to action either on the muscle, the nerve trunks, or the intermediate structures. That it is not due to the muscle is shown by the fact that direct stimu- lation causes the same movement as usual. On the other hand, in the experiment in which the artery is ligatured, stimulation of the nerves above the ligature, that is, where the poison has access to the nerve fibres, causes contraction, so that the nerve trunks do not seem affected. This may be shown in another way ; if a nerve-muscle preparation be made and the nerve be laid in a solution of curara, contraction of the muscle still occurs on stimulation of the nerve, but if the muscle be laid in the curara solution stimulation of the nerve has no effect while direct stimulation still causes contraction. Curara must, therefore, act on the connection between the nerve and muscle within the muscle it- self, that is, on the terminations of the nerve in the muscle. Curara paralyzes the nerve terminations without previous stimulation. Here, perhaps, better than elsewhere it can be shown that the condition of ' ' paralysis ' ' produced by poisons is analogous to that termed by physiol- ogists " fatigue." It is known that on stimulating a nerve rapidly by elec- tric shocks, or otherwise, the muscle at first contracts with every stimulation, but eventually ceases to respond, owing to l i fatigue ' ' of the nerve ends, that is, to their inability to transmit impulses from the nerve to the muscle. If now the response to nerve stimulation of a muscle to which a minute quantity of curarine has been applied, be compared with that of a normal one, it is found that the poisoned one ceases to respond much sooner than the other i. e. , its nerve ends become fatigued much sooner. The more cu- rara is applied, the sooner does it fatigue, until at last no response at all can be elicited from it. The " paralysis" of the nerve terminations by curara then is of the same nature as physiological " fatigue," and other conditions of " paralysis " are also analogous to those produced by over-stimulation, though the exact condition of the paralyzed organ may not be the same as the fatigued one. Thus there is some reason to suppose that in the curarized 256 ORGANIC DRUGS ACTING AFTER ABSORPTION. terminations the energy consumed in transmission is present, but in such a form that it cannot be changed to actual movement, while in fatigue the energy has all been exhausted by the impulses which have already passed through. Curara paralyzes very readily the terminations of nerves in all striped muscular tissue except the heart. The nerves first affected are those of the short muscles of the toes, ear and eye, later those supplying the limbs, head and neck, and, last of all, those supplying the muscles of respiration. At first, slight movements can be performed, because single impulses can pass through the nerve ends, but sustained con- tractions such as are necessary to preserve the equilibrium, cannot be maintained, and the animal therefore falls. The intermittent impulses to the respiratory muscles still allow time in the interval for the re- covery of the terminations, but as the intoxication proceeds, the num- ber of impulses which can pass through becomes fewer and fewer, and the movement therefore assumes more and more the character of a jerk. Eventually total paralysis sets in and, unless artificial respiration is carried on, asphyxia follows. Small doses of curara do not affect the inner vation of unstriped muscle, and the strict demarcation of its action is seen very distinctly in organs which consist partly of striated and partly of unstriated fibres. Thus in the oesophagus, the striated muscle fibres no longer contract on stimulation of the vagus after curara, while the unstriated continue to respond as usual. In the iris of the mammals, which consists of unstriated muscle, curara has no effect, while the striated muscle of the bird's iris ceases to respond to stimulation of the motor oculi, but contracts on direct stimulation. The terminations of the nerves in the heart are not affected, as the cardiac fibre is not of the same character as the ordinary striated one, but the nerves of the lymph hearts of the frog are paralyzed, these organs consisting of ordi- nary striated muscle. Curiously enough, it has been found that curara does not act on the terminations of the motor nerves supplying the elec- trical organ of the torpedo, although this organ is analogous to striated muscle in many respects. The nerve ends in striated muscle in in- vertebrates also appears to be immune to curara (Straub). The nerve fibres seem unaffected by curara, for stimulation causes the usual electrical changes in them after it. The action of curara on the muscle fibres has been a good deal disputed, many authorities deny- ing that any alteration whatsoever occurs, while others assert that slight modifications may be observed. When larger quantities of curara or curarine are injected, several other organs are affected. Thus the Peripheral Ganglia cease to trans- mit impulses, and hence stimulation of the nerves central to them has little or no effect. In this way the stimulation of the vagus in the neck produces no slowing of the heart, because the impulses can no longer pass through the ganglionic structures on the course of the fibres, and stimulation of several secretory nerves, such as the chorda tympani, has no effect on the secretion. The sympathetic ganglia are also paralyzed by nicotine, which differs from curara in stimulating CURARA. 257 them previously, and also in attacking the ganglia before it affects the endings in muscle. Large quantities of curara are often said to paralyze the nerve terminations in unstriated muscle, but this has never been satisfactorily proved, all the symptoms quoted to show this effect being explained by the paralysis of the sympathetic ganglia, which undoubtedly occurs. Curara, then, first paralyzes the terminations of efferent or centri- fugal nerves in voluntary muscle, and in larger quantities the ganglia (c Nicotine). The peripheral terminations of the afferent or sensory nerves seem unaffected, for if the artery of one leg be ligatured before the application of curara, reflex movements may be obtained in it from stimulation of any part of the body, while if the sensory terminations were paralyzed reflexes could be elicited only by the irritation of parts to which the poison had not penetrated, i. e., from the ligatured leg. Very large quantities of curarine are said by Tillie to cause a stim- ulation of the Central Nervous System resembling that described under strychnine. In ordinary poisoning, however, no evidence of this stimulation is shown, as although an increased number of impulses may be sent out, they cannot reach the peripheral organs owing to the paralysis of the motor end-plates and of the ganglia. The Heart does not seem to be acted on directly by ordinary quan- tities of curarine, and the circulation is left intact long after the respiratory nerves have been paralyzed. Large quantities prevent the inhibitory action of the vagus, and the pulse is consequently quickened, but the blood-pressure often begins to fall at the same time, owing to the dilatation of the peripheral arteries through paralysis of the ganglia on the course of the constrictor nerves. After curara and curarine the movements of the Intestines are said to be increased. This was formerly supposed to be due to the asphyxia, but seems to be independent of it, for the increased peristalsis occurs even when artificial respiration is kept up, and, according to Nasse, the irritability of the bowel muscle is much increased by curara. A similar accelera- tion of the rhythmic movements of the spleen has been noted after curara by Shafer and Moore. The Secretions sometimes seem to be increased by curara, for tears, saliva and perspiration may be formed in considerable excess of the rormal. Metabolism. The cessation of the ordinary movements after curara and under artificial respiration has generally been accompanied by a marked decrease in the oxygen absorption and the carbonic-acid excre- tion, but Frank and Gebhard state that this is not the case when the temperature is maintained by the application of heat. Sugar and lactic acid are often found in the urine after curara, but this is due to partial asphyxia and not to the direct action of the poison ; the glycogen of the liver and muscles disappears from the same cause. Curara is excreted by the kidneys apparently unchanged. It has long been known that this arrow poison may be swallowed with impu- nity, provided there is no wounded surface in the mouth or throat and 17 258 ORGANIC DRUGS ACTING AFTER ABSORPTION. that it is therefore perfectly safe to suck the poison from a wound. This has been explained in various ways, some holding that the ab- sorption from the stomach is so slow that the kidneys are able to ex- crete the poison as fast as it reaches the blood and that this prevents its accumulation in sufficient quantity to affect the tissues. Others suppose that the liver retains and destroys it and a third view is that it is ren- dered innocuous in passing through the stomach walls. Rothberger has recently shown that curara and physostigmine are mutually antagonistic so far as the action on the nerve terminations in striated muscle is concerned (see Physostigmine). Curine, the second alkaloid found by Boehm in some specimens of curara, is a much less poisonous body than curarine. It possesses some action on the heart, the same appearances following its injection in the frog as after digitalin and veratrine, while in mammals the rhythm is slow even after paralysis of the inhibitory mechanism. PREPARATIONS. Curara, an extract of varying constitution and strength. The active con- stituents are freely soluble in acidulated water, and when used ought to be injected hypodermically. Before using curara in therapeutics it is always necessary to estimate the strength of the preparation by experiments on animals, and its application ought to be graduated, commencing with the smallest quantities and increasing them until the desired effect is attained. Neither curara nor its alkaloids are official. Therapeutic Uses. Curara has been used occasionally in various condi- tions of exaggerated movement, such as tetanus, strychnine poisoning and hydrophobia. The object is to lessen the movement by partial paralysis of the motor terminations. The respiratory nerves being the last to be affected by the poison, the convulsions may be controlled, or at any rate hindered from causing such marked irregularity of the respiration as they would otherwise do, and in the same way the overstrain of the heart caused by the convulsions may be prevented. The danger accompanying the use of curara is great, however, and the fact that in all these cases the cause of the move- ment is excessive activity of the central nervous system would seem to indi- cate one of the many depressants of that system, rather than a drug such as curara, whose action is on an entirely different part of the body. Some cases of tetanus and one of hydrophobia are alleged to have been successfully treated by it, but its use must still be regarded as purely experimental, and, in fact, as generally opposed to the teachings of rational therapeutics. Paralysis of the terminations of the motor nerves in striated muscle the so-called " Curara- Action " is elicited by a large number of poisons, but in few of them is it the first effect of their application. Many drugs induce it only when injected in large quantities and at the end of a series of phenom- ena produced by their action on other parts of the body ; it is observed much more frequently in frogs than in mammals, and is often of little importance compared to the other symptoms. Among the bodies which resemble curara more closely in their action, the peripheral paralysis playing the chief role in their effects, are the ammonium compounds formed from the natural alkaloids by the substitution of an alkyl, e. g., methylstrychnine, amyl quinine, etc. 1 Some of the ammonium salts and many of the alkyl ammonium combinations also cause it, so that the general statement may be made that quaternary 1 Boehrn has recently stated that tubocurarine, which is the active constituent of much of the modern curara, is really one of those methyl bases (methylcurine). CONIINE, GELSEMININE AND SPARTEINE. 259 compounds of nitrogen possess a curara action ; in these the nitrogen atom may be replaced by phosphorus or arsenic without loss of the curara action, so that nitrogen is not a necessary constituent of substances possessing this property. The simpler bodies, pyridine and quinoline which form the basis of most of the natural alkaloids, have little action save on the nerve ends, a fact w T hich is of some importance in the consideration of the relation between the chemical constitution and the pharmacological action of poisons. At the same time the property of causing this paralysis is so widespread among substances of very different constitution that it may be looked upon as in- dicating a peculiar susceptibility and weakness of the motor terminations, more especially in the lower vertebrates, and inferences based upon it as to the mutual relation of substances are to be received with caution (San- tesson). BIBLIOGRAPHY. Cl. Bernard, Comptes rendus, xxxi., p. 533; xliii., p. 825. Kolliker. Virchow's Archiv, x., p. 3. Boehm. Beitrage zur Physiologie C. Ludwig zu seinem sechzigsten Geburtstage gewidmet, Leipzig, 1887, p. 173. Arch, der Pharmacie, ccxxxv., p. 660. Overend. Arch. f. exp. Path. u. Pharm., xxvi., p. 1. Tillie. Ibid., xxvii., p. 1. Boehm. Ibid., xxxv., p. 16. Santcsson. Ibid., xxxv., p. 23. Skand. Arch. f. Physiol., x. and xi. Saner. Pfluger's Arch., xlix., p. 423. Nikokki u. Dogiel Ibid., xlvii., p. 68. Jakabhazy. Arch. f. exp. Path. u. Pharm., xiii., p. 10. Morishima. Ibid., p. 28. Straub. Pfluger's Arch., Ixxix., p. 379. Meyer. Ergebnisse der Physiol., i. (2), p. 200. Frank and Gebhard. Ztschr. f. Biol., xliii., p. 117. X. CONIINE, GELSEMININE AND SPARTEINE. Several alkaloids which show many points of resemblance to curara in their pharmacological effects, may be classed together, although their action may diifer in details. Coniine. Coniine is one of the simpler derivatives of Piperidine, which is obtained from Pyridine by reduction. A series of alkaloids may be formed from piperidine by substituting methyl, ethyl, propyl or other alkyls for hydrogen, and one of these, a-propyl-piperidine, is the natural alkaloid coniine. Pyridine. Piperidine. Coniine. CH CH CH NH NH Coniine is found in Hemlock (Conium maculatum), along with two nearly allied alkaloids, Methyleoniine and Conhydrine. The latter dif- fers from coniine only in having a hydroxyl group in the side chain. Methyleoniine is found in many specimens of coniine, and is probably formed in the plant, although this has not been definitely proved ; in 260 ORGANIC DRUGS ACTING AFTER ABSORPTION. it the hydrogen attached to the nitrogen of coniine is replaced by methyl. Coniine is of some historical importance, as the first vegetable alkaloid which was successfully formed by synthesis in the laboratory. It is a volatile fluid, characterized by a strong mouse-like odor, but forms crystalline, non-volatile salts. The two other alkaloids of hem- lock act in the same way as coniine, although much more weakly, so that the effects of the crude preparations of the plant are identical with those of coniine. Piperidine and its compounds with methyl and ethyl-act in the same way as coniine but more weakly. An ascending scale of toxicity may be formed, commencing with piperidine and passing upwards through methyl- and ethyl-piperidine to coniine. The other simple derivatives of piperidine seem to resemble coniine in their action as far as it has been investigated. Symptoms. The general symptoms induced in man by poisonous doses of coniine are weakness, languor and drowsiness which does not pass into actual sleep. The movements are weak and unsteady, the gait is staggering, and nausea and vomiting generally set in, along with profuse salivation. In most cases the intelligence remains clear to the end, as is related of the death of Socrates from hemlock poisoning, but in some instances imperfect vision and hearing have been noted. The pupils are somewhat dilated. Tremors and fibrillary contractions of the muscles are often seen in animals, and some observers state that actual convulsions occur. The breathing becomes weaker and slower and death occurs from its arrest. Action. Coniine is sometimes credited with possessing a narcotic depressant action on the Central Nervous System, but this is by no means a characteristic feature in poisoning, for in both man and animals consciousness is often retained until immediately before the cessation of the respiration. Other writers mention convulsions as a feature of coniine poisoning, and weak convulsive movements are often seen before death, obviously from the failure of the respiration. Quite distinct from these are the twitching and tremors of the earlier stages of the intoxication, which are often accompanied by a certain stiffness and rigidity of some of the muscles of the limbs. Some of these movements may be due to the partial paralysis of the motor nerve terminations preventing the animal from contracting its mus- cles in a normal tetanus and permitting only of short, jerky move- ments, which may readily be mistaken for convulsions. But at the same time, the tremor and the rigidity of the limbs seem to indicate some central stimulation, although this point requires further investi- gation. This preliminary stimulation may afterwards pass into de- pression of the lower parts of the central nervous system, although this is denied by some investigators, who maintain that coniine has little or no central action, but manifests its activity only in the peripheral organs. Coniine causes nausea and very often vomiting at an early stage of its action. This may be elicited by its hypodermic or intravenous in- CONIINE. 261 jection, and is probably due to an alteration in the medullary centres rather than in the stomach. The nausea is accompanied by profuse salivation and sometimes by perspiration. The chief effect of coniine in the frog is a paralysis of the Termina- tions of the Motor Nerves similar to that induced by curara. This paralysis is elicited only with difficulty in the mammal, but unques- tionably occurs to a more or less marked extent. According to some researches on the subject, all the symptoms in mammals are due to the paralysis of the ends of the motor nerves, while others regard both the convulsions and the final failure of the respiration as of central origin. It seems likely that while in the frog the symptoms are all due to the action on the nerve terminations, some of the phenomena observed in mammals are due to central stimulation and to subsequent paralysis of the medullary centre of respiration. It is difficult to explain on any other theory how the symptoms of coniine poisoning are so different from those of curara. Coniine acts on the Peripheral Ganglia in the same way as curara. According to some writers these are first stimulated and then para- lyzed, and there seems to be no question as to the final paralysis, whether the preliminary stimulation is present or not. Coniine cer- tainly does not act so strongly on the ganglia as nicotine, and the details of the action may, therefore, be left for discussion under that heading. (See page 274.) The inhibitory impulses no longer reach the heart after large doses of coniine, owing to paralysis of the gang- lionic apparatus and stimulation of the vagus nerve has no effect on the pulse rate. Some drugs which act on the extreme terminations of the inhibitory fibres still slow and weaken the heart, however. Simi- larly, stimulation of the cervical sympathetic no longer dilates the pupil, because the superior cervical ganglion is paralyzed. The partial dilatation of the pupil in cases of poisoning may, perhaps, indicate a similar action on the ciliary ganglion. Coniine seems to have but little direct effect on the Heart though large quantities slow the rhythm and somewhat prolong the systole in the frog (Moore and Row), and some slowing of the mammalian heart has been noted from the intravenous injection of large quantities. The inhibitory mechanism is often found to be stimulated and the pulse is accordingly somewhat slow and weak. The paralysis of the ganglia on the inhibitory nerve may lead to some acceleration in other cases, but the changes in the heart are not marked features in the intoxica- tion. Moore and Row have observed a very considerable though transient increase in the arterial tension after coniine, and regard it as of pe- ripheral origin, for they found that the perfusion of coniine through the blood vessels of the frog tends to constrict them, while the direct application to the exposed blood vessels has no such effect, but rather widens their calibre. They are accordingly inclined to regard the rise of blood-pressure as due to a stimulation of the ganglionic apparatus lying on the course of the vaso-constrictor nerves. 262 ORGANIC DRUGS ACTING AFTER ABSORPTION. The Respiration is generally accelerated and deepened in the earlier stages of the coniine intoxication, but later becomes slow and labored, then weak and irregular, and finally ceases while the heart is still strong and the consciousness has just disappeared. The cause of the asphyxia is still undecided, many investigators holding that the centre is paralyzed before the terminations of the nerves in the diaphragm, while the ma- jority of recent investigators look upon the paralysis of those termina- tions as the cause of death. A curious change has been observed by Giirber in the Blood Cells of frogs poisoned with coniine. Numerous small vacuoles appear in the red corpuscles, and persist long after the frog shows no further symp- toms of poisoning. The nucleus is also somewhat altered, but not so characteristically. Coniine is rapidly excreted in the urine, so that its action passes off very soon even when quite large doses are taken. The treatment of coniine poisoning therefore consists in evacuation of the stomach and artificial respiration. Piperidine acts in the same way as coniine, but more weakly, while methyl- and ethyl-piperidine stand between them in toxicity.. Many of the piperidine alkaloids cause the formation of vacuoles in the red blood cells of the frog, and the simpler members of the series act more strongly in this direction than the more complex ones, while they are much less active as general poisons. Pyridine resembles piperidine in most features but does not paralyze the ganglia nor increase the blood-pressure. It seems more poisonous in frogs, and induces distinct depression of the central nervous system, but like piperidine it is only feebly poisonous in mammals. Pyridine is excreted in the urine as methyl-pyridine, a combination between it and the alkyl occurring in the tissues. A similar synthesis occurs between methyl and telluric acid (see Tellurium). Quinoline and isoquinoline cause in mammals a condition of col- lapse similar to that seen under the antipyretics and the benzol com- pounds. PEEPAEATIONS. Conium (U. S. P.), Conii Fructus (B. P.), the dried, full-grown, unripe fruit of Conium maculatum, or hemlock. Fluidextractum Conii (U. S. P.), 0.1-0.5 c.c. (2-8 mins.). Tinetura Conii (B. P.), -1 fl. dr. Conii Folia (B. P.), the fresh leaves and young branches of Conium mac- ulatum, collected when the fruit begins to form. Succus Conii (B. P.), juice of hemlock, in which one part of alcohol is added to three of the juice, 1-2 fl. drs. Unguentum Conii (B. P.). Therapeutic Uses. Conium has passed into almost complete disuse, It has been prescribed in whooping-cough and chorea with doubtful results, and has been employed locally and given internally to relieve pain. Tetanus and strychnine poisoning have been treated with it without apparent results. GELSEMIUM. 263 BIBLIOGRAPHY. Guttmann. Berl. klin. Woch., 1866, p. 45. Kolliker. Virchow's Arch., x., p. 235. Prevost. Arch, de Physiol. (2), vii., p. 40. Boehm. Arch. f. exp. Path. u. Pharm., xv., p. 432. Hayashi and Muto. Ibid., xlviii., p. 356. Gurber. Arch. f. Anat. und Phys., 1890, p. 401. Cushny. Journ. of Exp. Med., i., p. 202. Moore and Row. Journ. of Phys., xxii., p. 273. Stockman. Journ. of Phys., xv., p. 245. Bruntonand Tunnicliffe. Ibid., xvii. , p. 272. Heinz. Virchow's Arch., cxxii., p. 116. His. Arch. f. exp. Path. u. Pharm., xxii., p. 253. Cohn. Zts. f. phys. Chem., xviii., p. 112 ; xx., p. 210. Gelsemium semper virens (Yellow Jasmine or Carolina Jasmine) contains two alkaloids, Gelsemine and Gelseminine. 1 Gelsemine forms crystalline salts, while gelseminine is entirely amorphous, and, as far as is known, does not form any crystalline combinations. Gelsemine is only slightly active, inducing the same symptoms in frogs as strych- nine, but having no effects on mammals, even when injected into a vein in very large quantity. Gelseminine, on the other hand, is a powerful poison which resembles coniine in most of its effects. The action of the crude preparations of gelsemium is undoubtedly due to gelsemi- nine and not to gelsemine, as far as mammals are concerned. Large quantities of the extract injected into frogs may, however, increase the reflex movements somewhat from the gelsemine they contain. Action. The symptoms of gelsemium poisoning resemble those of coniine so closely that the reader may be referred to the description given under the latter. Grelseminine differs from coniine chiefly in possessing a more depressant action on the central nervous system. In the frog the spinal cord is distinctly less active than usual before the ends of the motor nerves are paralyzed, and, in fact, the depression of the central nervous system seems to be the cause of the general paralysis in these animals, rather than the peripheral action, although this is always present. In mammals the symptoms resemble those of coniine more closely than in the frog, and there may be some ques- tion as to whether the effects are mainly central or peripheral in ori- gin. There is a general consensus of opinion, however, amongst those who have worked on the subject, that gelseminine proves fatal by para- lyzing the respiratory centre rather than the terminations of the nerves in the diaphragm and other muscles, while most writers now consider the asphyxia of coniine poisoning due to the peripheral action. The symptoms are practically identical, however, and it will probably be found that both act on the same points in the innervation of the respi- ration. In the meantime the question must remain undecided for both poisons. The pupil is very widely dilated by gelseminine when a solution is 1 Gelsemine is frequently known as gelseminine, a use of the term which leads to some confusion, and which is not based on the history of the drug. 264 ORGANIC DRUGS ACTING AFTER ABSORPTION. applied locally to the eye, much less so in general poisoning, in which the respiration generally fails before the pupil is fully dilated. The power of accommodation is also entirely lost when gelseminine or gel- semium tincture is applied to the eye. This mydriatic effect has not been explained, but the most plausible suggestion would seem to be that gelseminine paralyzes the terminations of the oculomotor nerve in the eye in the same way as atropine. Gejs^mjmne differs from atro- pine in its behavior to other nerves, however, for it paralyzes the inlrib- jtojrv cardiac fibres and the chorda tympam through acting on tne gan- gliomc^siniotrires on their course and nof on the extreme terminations. Its action oiyiie^ganiglia, as far as it is known, resembles that of coniine, but it does not cause "any increase in the arterial tension, such as is observed under this poison. PREPARATIONS. Gelsemium (U. S. P.), Gelsemii Radix (B. P.), the dried rhizome and roots of Gelsemium sempervirens or nitidum. Fluidextractum Gelsemii ( U. S. P.), 0.3-0.6 c.c. (5-10 mins.). Timtura Gelsemii (U. S. P., B. P.), 0.3-1 c.c. (5-15 mins.). " Gelsemine " is an unofficial mixture of the alkaloids in very varying pro- portions. In some preparations no gelseminine whatever was found. Therapeutic Uses. The tincture of gelsemium has been employed as a nr^driatic in ophthalmology, but it presents no advantages over the more generally used preparations of atropine, and sometimes causes some pain and redness, which has prevented its general adoption for this purpose. In certain forms of ngyxajgja, especially of the facial branches of the trigeminus, gelsemium has proved of some value, when administered internally as the tincture. BIBLIOGRAPHY. Ringer and Murrell. Lancet, 1876, i., p. 82. Putzeys and Romiee. Memoire sur 1' action physiologique de la Gelsemine. Bruxelle, 1878. Cushny. Arch. f. exp. Path. u. Pharm., xxxi., p. 49. Sparteine^ Another alkaloid which resembles coniine closely in its action is Sparteine, which is found in the common broom plant (Spartium or Cytisus scoparius), along with a neutral substance, Scoparin. Spar- teine * is a pyridine derivative possessing the formula C 15 H 26 N 2 , and is a fluid, but forms crystalline salts, which are often prescribed instead of the crude preparations. Action. The general effects of sparteine are almost identical with those of coniine, but it seems very probable that the central nervous system is little affected by it, the whole of the phenomena pointing to a paralysis of the peripheral terminations of the motor nerves and probably of the terminations around the cells of the sympathetic gan- glia. Sparteine has more effect than coniine on the heart, which it 1 Sparteine also occurs in the black and yellow lupines along with lupinine. SPAtiTEtNE. 265 [epresses so that the rhythm is slow and the contractions weak. I len injected into a vein, sparteine induces less increase in the arterial! jsion than coniine, probably because the contraction of the vessels! counterbalanced by the weakness of the heart. No increase in the' arterial tension is observed from the administration of sparteine inter- nally, and even the slight rise of pressure induced by intravenous in- jection is of only short duration. The slow pulse and slight rise of pressure observed in experiments in animals when sparteine is injected intravenously, have led some writers to ascribe to it an action similar to that of digitalis, and at one time sparteine was used to some extent as a substitute for the latter ; both experimental and clinical observations, however, go to show that these claims are quite unfounded, and sparteine is compara- tively little used at the present time, and possesses no properties which are likely to reinstate it in favor. Sparteine is very much less poisonous than either coniine or gelsemi- nine. It proves fatal to animals by paralyzing the terminations of the phrenic nerves in the diaphragm. Broom tops have long enjoyed a certain reputation as a diuretic, and this perhaps strengthened the belief in the virtues of sparteine as a heart remedy. The diuresis is not due to the sparteine, however, but to the scoparin, which seems to act on the renal epithelium in the same way as Uva-ursi and other remedies of that series. The broom tops are generally administered in the form of a decoction or infusion, and the large amount of water taken along with them may also tend to increase the urine and to strengthen the reputation of the remedy. PREPARATIONS. Scoparius (U. S. P.), Scoparii Cacumina (B. P.), the tops of Cytisus sco- parius or broom. Infusum Scoparii (B. P.), 1-2 fl. oz. Succus Scoparii (B. P.), 1-2 fl. drs. ^Sparteinse Sulphas (U. S. P.) (C 15 H 26 N 2 H 2 SO, + 4H 2 O), colorless, white crystals with a saline bitter taste, very soluble in water and alcohol. The dose recommended by different clinicians as of benefit in heart disease varies from 0.004-0.8 G. ( T V-12 grs.) in the course of 24 hours. It may be given in doses of 0.1 G. (2 grs.) with perfect safety. Uses. Broom tops are used as a feeble diuretic, generally in the form of a decoction (16 G. in 250 c.c. of water, or J oz. in a half pint in divided doses in 24 hours), or infusion (B. P.). Sparteine has been advised in heart disease, but is of no value here. It has also been proposed to paralyze the terminations of the vagus with it before the administration of chloroform, the object being to avoid the reflex syncope, but a small dose of atropine would be preferable. It has also been suggested as a local anaesthetic in ophthalmology, but has only a feeble action. BIBLIOGRAPHY. Pick. Arch. f. exp. Path. u. Pharm., i., p. 397. Masius. Bull, de 1'Acad. Koy. de Med. de Beige, 1887. Oushny and Matthews. Arch. f. exp. Path. u. Pharm., xxxv., p. 129. Muto and Ishizaka. Ibid., 1., p. 1. 266 ORGANIC DRUGS ACTING AFTER ABSORPTION. XI. NICOTINE AND LOBELINE. Nicotine, the well-known alkaloid of tobacco (Nicotiana tabacum), is a volatile fluid, possessing a strong alkaline reaction, and forming salts with acids, most of which are amorphous. It is a combination of pyridine with a hydrated pyrrol ring as shown by the structural formula Nicotine is the only constituent of tobacco which possesses any toxicological interest, although several other alkaloids are present in comparatively small amounts. It is accompanied by a volatile oil in dried tobacco, but this is only developed during the processes of pre- paration and seems to have no action apart from that of the other vola- tile oils. The odor and flavor, and probably the " strength," of to- bacco depends in part upon the quantity and quality of this oil, in part on some products of the decomposition of nicotine. Absolutely pure nicotine has comparatively little odor, but it decomposes when kept, becomes dark colored and acquires the characteristic odor of tobacco. Another alkaloid which is practically identical with nicotine in its pharmacological action is Piturine (C 12 H 16 N 2 ), which is derived from the pituri plant (Duboisia Hopwoodii). The leaves of the pituri are said to be used by the Australian natives in the same way as tobacco by the civilized races. Lobeline (C 18 H 23 NO 2 ), an alkaloid obtained from Lobelia inflata or Indian Tobacco, resembles nicotine very closely in its action, and may be discussed along with it. Tobacco is not used in therapeutics, but is of great hygienic im- portance, and nicotine possesses considerable biological interest from the results obtained by Langley by its use in physiology in recent years. Lobelia has a somewhat restricted field of usefulness in therapeutics, in which it is prescribed in asthma. These alkaloids act chiefly on the central nervous system, the sympathetic ganglia, and the terminations of the motor nerves. Symptoms. Poisonous doses administered to man or other mam- mals cause a hot, burning sensation in the mouth, which spreads down the oesophagus to the stomach, and is followed by salivation, nausea, vomiting and sometimes purging. The breathing is quick, deep and labored, and is often accompanied by moist rales. The pulse is gen- erally slow and somewhat weak at first and then becomes very rapid, but after very large doses may be first accelerated and then slow and NICOTINE AND LOBELINE. 267 feeble. Some mental confusion, great muscular weakness, giddiness and restlessness are followed by loss of coordinating power and partial or complete unconsciousness. Clonic convulsions set in FIG. 24. later, accompanied by fibril- lary twitching of various muscles, and eventually a tetanic spasm closes the scene by arresting the res- piration. In other instances the convulsions are followed by complete relaxation of all parts of the body, the reflexes disappear, the res- piration becomes slow and weak and finally ceases, the heart continuing to beat for some time afterwards. Very large doses of nico- tine may prove fatal within a few seconds ; the symp- toms are those of sudden paralysis of the central nervous system including the respiratory centre, and no convulsions are de- veloped. In the frog the same ex- citement and violent convul- sions are seen as in mam- mals, but the respiration SOOn Ceases, and there fol- Diagram of the regulating nerves of the heart. P, inhib- , , . ,, itory fibres arising in the vagus centre in the medulla ob- lOWS a Cataleptic Stage longata and terminating around ganglion cells in the auricle i . i . i . -, (A). The axis cylinders issuing from these cells terminate in Which tile animal assumes on the muscular "fibres of the auricle and ventricle ( V). R, offifn/l accelerator fibres issuing from the spinal cord and termi- attitude. na ting around ganglion cells in the stellate ganglion G. The lorrc QTVI nrrccorl in axis fibres of these ganglion cells run through the Annulus 1 Vieussenii and terminate on the muscular fibres of the auri- front Of the Sternum, and cle and ventricle. N, y points at which nicotine, coniine, . . curanne, etc., act the ganglion cells surrounded by the are rigid, the thighs are at terminations of the nerves. M, points at which muscarine . -. , , . n and atropine act the terminations of the fibres which arise right angles to the aXIS OI from the intra-cardiac ganglia. the body and the legs are flexed on them but are not rigid. When a leg is drawn down it at once returns to its original position, and the frog still attempts to escape when it is aroused. Fibrillary contractions are observed in many of the muscles. Somewhat later, the reflexes disappear, the muscles become flaccid, and eventually complete paralysis occurs from a curara-like action on the terminations of the nerves. Nicotine has but little toxic action on the lowest invertebrates, but as the nervous system begins to be differentiated it causes paralysis, 268 ORGANIC DRUGS ACTING AFTER ABSORPTION^. and still higher in the scale the paralytic action is preceded by a stage of stimulation. Circulation. The action on the circulation is extremely complex, as a number of factors are involved. After moderate quantities the heart is slow and may stand still in diastole for a few seconds, but then recovers gradually and regains its former rhythm or becomes somewhat quicker. The slow pulse is due to stimulation of the ganglia on the vagus nerve (Fig. 24, N), exactly the same effects being produced as by stimulation of the vagus fibres in the neck. It is not affected by section of the cervical pneumogastric, as the path from the ganglia to the cardiac muscle fibres is still intact, but on the other hand, it is pre- vented by atropine, which acts on the extreme terminations of the in- hibitory fibres, and therefore blocks the passages of impulses from the ganglia to the muscle. It is also prevented by a number of drugs, such as curara and coniine, which paralyze the ganglia. This stimulation of the ganglia is of but short duration, soon passing into paralysis, which obstructs the passage of the inhibitory impulses from above. On stimulating the vagus after nicotine there is conse- quently no slowing of the heart but often some acceleration, due to the fact that the accelerating fibres running along with the inhibitory in the vagus nerve have no ganglionic apparatus in the heart, and are therefore unaffected by nicotine. Although inhibitory impulses can no longer reach the heart from above, the intracardiac inhibitory neuron is still intact, and stimulation of the venous sinus in the frog still causes arrest of the heart exactly as in the normal animal. The stimulating current here reaches the inhibitory nerves beyond the paralyzed ganglia (Fig. 24, X\ and these preserve their usual irrita- bility. In the same way a number of poisons which act upon the extreme terminations of the inhibitory fibres in the heart muscle (Fig. 24, M ) can slow the rhythm even after the ganglia have been paralyzed by nicotine (see the Pilocarpine and Muscarine group). The results of the stimulation and subsequent paralysis of the ganglionic structures on the inhibitory fibres by nicotine are the preliminary slow- ing and subsequent slight acceleration of the heart rhythm seen in both cold- and warm-blooded animals. In larger doses nicotine produces no slowing of the heart, owing to the ganglia being paralyzed imme- diately, without previous stimulation. In addition to its action on the peripheral inhibitory ganglia, nico- tine seems to stimulate the vagus centre in the medulla, as the slow- ing is greater when the vagi are intact than when they are divided. But apart from this action on the inhibitory apparatus, nicotine pos- sesses some direct action on the heart muscle, which appears to be first stimulated and then depressed. Accordingly, when the inhibitory appa- ratus has been previously paralyzed, moderate quantities increase the rate of the heart beat considerably, while very large ones slow and weaken it. It has been supposed that this quickening is due to action on the accelerator centre, or on the ganglia on the course of the sym- pathetic accelerator fibres (N', Fig. 24), but this seems not to be the NICOTINE AND LOBELINE. 269 only cause, for Wertheimer found the acceleration continue even after extirpation of these ganglia. The quickening must be attributed in part, or wholly to action on the cardiac muscle, or on the termina- tions of the accelerator nerves in it. The subsequent slowing and weak- ness is undoubtedly due to a paralyzing action on the muscle itself. On the injection of nicotine into a vein or subcutaneously an im- mense augmentation of the arterial tension occurs ; this may be due in part to stimulation of the vaso-constrictor centre in the medulla, but is to be ascribed chiefly to peripheral influences, for it has been ob- served after section and even after total removal of the spinal cord. The vaso-constrictor nerves pass through ganglia on their way to the vessels and the rise of the blood-pressure seems to be mainly caused by a stimulation of these ganglia. The constriction of the vessels can be observed in many parts of the body mesentery, foot, rabbit's ear, etc. In these parts the pallor produced by the narrowing of the vessels is followed by redness and congestion owing to the paralysis of the ganglia, and at the same time the pressure falls to a level somewhat below the normal. In some parts of the body no constric- tion of the vessels occurs ; for example, the dog's lip and mouth are con- gested first and then become pale. This flushing seems partly due to the stimulation of the ganglionic apparatus on the vaso-dilator fibres for these parts, but cannot be wholly explained thus, for it occurs also after removal of the superior cervical ganglion, although to a less marked degree. It may therefore be caused in part by direct action on the vessels. After a few minutes the blood-pressure falls to the normal level or lower, but a second injection again produces a similar rise in the arterial tension, unless the first was large enough to paralyze the ganglia. Eventually nicotine lowers the blood-pressure owing to the weakening action on the heart. Respiration. The respiration is at first rapid and shallow with some deficiency in the expiratory movements, but after a time, while main- taining the acceleration, it becomes deeper. It is liable to be interrupted at this stage by the convulsions, but if these do not prove fatal, it gradually becomes slower while remaining deep. Later, pauses in the position of expiration appear, and the movements become weaker until they disappear, the animal dying of asphyxia. The rapid, shallow movements in the beginning of the intoxication are absent in animals in which the pneumogastric nerves have been previously divided, so that this phenomenon appears to be due to the alkaloid acting as an irritant to the pulmonary branches of the pneumogastric. The later features are caused by its acting on the respiratory centre directly, first stimulating and then paralyzing it. After large doses this direct action alone may be elicited. The paralysis of the respiration is the cause of death, the heart continuing to beat for some time afterwards al- though slowly and weakly. The bronchial muscle relaxes after a transient constriction when nicotine or lobeline is ingested, these changes being brought about by stimulation and subsequent depression of the ganglia on the course of the innervating fibres. The dilatation of the bronchi is more marked when they have been previously in a state of constriction (Dixon and Brodie). 270 ORGANIC DRUGS ACTING AFTER ABSORPTION. FIG. 25. Most of the Secretions are increased temporarily by nicotine. The glands investigated have generally been the salivary, where it is found that the secretion is increased by the injection of small quantities, but is afterwards depressed, while large doses diminish it at once. The seat of action is again the ganglionic ap- paratus on the secretory nerves. If the chorda tympani be stimulated in the normal animal a large secretion of saliva at one follows, but if a sufficient quantity of nicotine be in- jected no such effect follows its stimulation. ' If, however, the nerve fibres be stimulated between the ganglion cells and the gland (at X in Fig. 25), the secretion again fol- lows as before. On the other hand, nicotine increases the secretion whether the chorda be intact or not, but ceases to act if the connection between the ganglion cells and the gland be inter- rupted. These results can only be in- terpreted by nicotine first stimulating and then paralyzing the ganglia on the course of the chorda tympani. In the same way it first stimulates and then paralyzes the ganglia which lie in the course of the sympathetic salivary fibres. Pilocarpine and muscarine cause profuse salivation after nicotine, because they stimulate the terminations of the nerves in the gland cells, and it is therefore immaterial whether the connection with the central nervous system be interrupted or not. On the other hand, the reflex secretion of saliva normally produced by irritation of the mouth or by chewing is prevented by nicotine. Atropine stops the secretion produced by nicotine by paralyzing the extreme terminations of the nerves. The other secretory glands are affec- ted in the same way by nicotine, and although the details have not been worked out so carefully as for the sali- vary glands, there is no question that their secretions are first in- creased by the stimulation of the ganglia on the course of their secretory nerves, and then lessened by their paralysis. Thus the Diagram of theinnervation cf the sub- maxillary gland. P, a fibre of the chorda tympani issuing from the pons Varplii and after "a devious course terminating around a ganglion cell in the hilus of the submaxillary gland. The axis from this ganglion cell runs to the secretory epi- thelium. 7?, a fibre issuing from the spinal cord and after running through the sym- pathetic chain in the neck, terminating around a ganglion cell in the superior cer- vical ganglion G. The axis from this cell runs to the secretory epithelium. In the diagram the nerves are represented as running to separate acini. N, N', gang- lion cells surrounded by the termina- tions of the nerves the points at which nicotine acts. M, the terminations of the secretory fibres connected with the chorda tympani the points at which atropine, muscarine, and pilocarpine act. NICOTINE AND LOBELINE. 271 sweat secretion is found to be markedly increased, as also the secretion of the bronchial mucous glands. The urine and bile have not been shown to be affected by nicotine, and as their secretion does not seem to be so dependent upon nervous influences, it is probable that it is but little changed in amount. Nicotine produces extreme Nausea and Vomiting when taken even in comparatively small quantities, a fact which is generally recognized by tyros in smoking. This may be in part central in origin, but is mainly due to the powerful contractions of the stomach walls. This contraction extends throughout the intestinal tract, so that repeated Evacuation of the Bowel occurs. Somewhat larger quantities may lead to a tetanic contraction of the whole intestine with almost complete obliteration of the lumen. This exaggeration of the peristaltic contraction is probably due to stimula- tion of the motor nervous apparatus in the intestinal wall, and a subse- quent paralysis of these structures leads to a failure of local stimuli to induce peristalsis. A further effect of nicotine in the bowel is due to its stimulating the ganglia on the fibres of the splanchnic which inhibit the rhythmical pendulum movements. These are arrested by the injection of nicotine, but return in exaggerated form as the gan- glionic stimulation passes into paralysis. The mesenteric vessels are narrowed at first from stimulation of the ganglia on the course of the vaso-constrictor nerves, but congestion follows the depression of these ganglia and the consequent fall in blood-pressure. Similar changes are produced by nicotine in the bladder and uterus, both of which are thrown into tetanic contraction. The urine is there- fore expelled very soon after the injection of nicotine, and this probably gave rise to the erroneous view that the renal secretion was increased. The action of nicotine on the Pupil varies in different animals, for while in the cat and dog its application either intravenously or locally produces marked but transitory dilation, in the rabbit partial con- striction sets in immediately. In cases of acute poisoning in man con- traction is generally seen at first and is followed by dilatation. In birds nicotine causes very marked contraction of the pupil, apparently owing to direct action on the muscles of the iris. The size of the pupil is regulated by two sets of nerves, the motor oculi and the sympathetic, and the ciliary fibres of both of these are interrupted by ganglia in their passage from the brain to the iris, those of the motor oculi by the ciliary ganglion, those of the sympathetic by the superior cervical ganglion (see Fig. 26, p. 287) ; the varying effects of nicotine may be due to its stimulating the one ganglion more strongly in one species of animals, the other in another. It is found, however, that atro- pine does not remove the effects of nicotine on the rabbit's eye, which would seem to indicate an action on the muscular fibres of the iris. Several other effects on the orbital muscles are seen ; thus in cats and dogs the nictitating membrane is withdrawn, the eye opens and is directed forwards, while in the rabbit these symptoms are preceded by a stage in which the nictitating membrane is spread over the cornea 272 ORGANIC DRUGS ACTING AFTER ABSORPTION. and the eye is tightly closed. These are probably produced by action on the superior cervical ganglion. Nicotine, then, first stimulates and later paralyzes all the Sympa- thetic Ganglia, whether applied locally to them or injected into the cir- culation. In these ganglia, the characteristic formation is the basket- like arrangement of the terminations of the entering nerve, which surround a large nerve cell from which an axis cylinder runs to the muscle or secretory cell. A nerve impulse from the central nervous system passes from the basket to the cell and thence to the periphery. Langley has recently shown that small quantities of nicotine stimulate the cell of the peripheral neuron, for the same effect is obtained from the application of the poison to the ganglion whether the basket-like terminations round the cell are normal or have degenerated. This renders it probable that the paralysis of the ganglia observed from larger quantities of nicotine is also due to action on the cell and not on the terminations. In the frog nicotine produces fibrillary contraction of the muscles, which is not prevented by previous division of the nerves leading to them, but disappears on the injection of curara ; on the other hand, the paralysis of the motor terminations by curara may be partially removed by small quantities of nicotine. This indicates that the fibrillary con- tractions arise neither from action on the central nervous system nor on the muscle itself, but from stimulation of the terminations of the motor nerves. These terminations are subsequently paralyzed if the quantity injected be large enough. In mammals the twitching of the muscles is prevented by section of the nerves, and is, therefore, due to central action, but large quantities of nicotine cause paralysis of the nerve ends exactly like curara. The nerves of the orbital muscles are found to be paralyzed sooner than those of the rest of the body. Nicotine does not seem to act on Muscular Tissue in general, although some obscure symptoms have been ascribed to changes in the cardiac and iris muscle. The convulsions seen in both cold- and warm-blooded animals evi- dence the influence of nicotine on the Central Nervous System. The spinal cord is thrown into a condition of exaggerated irritability, and the reflexes are correspondingly increased, but the convulsions do not seem to be due so much to the spinal cord as to the medulla oblongata and hind brain, for they are not tonic but clonic in character, and are much weaker after division of the cord immediately below the medulla than in the intact animal. The medullary stimulation also betrays itself in the rapid and deep respiration, and is perhaps in part respon- sible for the inhibitory slowing of the heart and the rise in the blood- pressure. The higher centres in the brain seem to participate but little in the stimulant action of nicotine, which is short-lived, and soon gives way to marked depression of the whole central nervous system, manifested in the slow respiration, the low blood-pressure, the disappearance of the reflex movements and the final unconsciousness. The Excretion of nicotine is probably carried on mainly by the NICOTINE AND LOBELINE. 273 kidneys, for it is found in the urine very soon after it enters the blood. It has also been detected in the saliva and perspiration. It has been shown repeatedly that nicotine and some other alkaloids are weakened in toxic effect or rendered entirely inactive by being mixed with an extract of the liver or of the suprarenal capsules ; but no satisfactory explanation is forthcoming, though there is every reason to suppose that much of the nicotine absorbed from the stomach and intestine is thus modified in its passage through the liver. When small quantities of nicotine are ingested repeatedly, the body soon gains a certain Tolerance, and no symptoms whatever are pro- duced by doses which would in ordinary cases produce grave poison- ing. A familiar example of this tolerance is seen in the practice of smoking. The first use of tobacco is in the great majority of indi- viduals followed by vomiting and depression which may even amount to collapse, but after a few experiences no symptoms follow smoking, owing to the cells of the body becoming tolerant of the poison. In some individuals no such tolerance is developed, and in every case the tolerance is much more limited and more difficult to acquire than that for morphine. In animal experiments it is often found that while one application of nicotine produces considerable ganglionic stimula- tion, the second has much less effect. This is probably due not to the establishment of tolerance, but to the first dose having produced primary stimulation and then depression of the ganglia, this depression, while not amounting to complete paralysis, being sufficient to counter- act to some extent the stimulant action of the second injection. Nicotine and Piturine are not used in therapeutics. Tobacco was formerly employed in the reduction of intestinal hernia, and for this purpose was injected into the rectum in the form of an infusion. Sev- eral cases of poisoning and the introduction of general anaesthesia led to its disuse. Tobacco. Tobacco had been in use among the aboriginal tribes of America before they became known to civilization. It was introduced into Europe soon after the discovery of America, and its use as an article of luxury, beginning in England, soon spread to the continent, and in spite of papal bulls and numerous efforts on the part of the secular authorities, has continued to enthral a considerable portion of the human race. The most widespread use of tobacco smoking is also the most ancient one, having been that of the aboriginal Indians. Snuff-taking, introduced by Francis II. of France, remained fashion- able for a long time, but is now almost obsolete. Tobacco-chewing is a more modern development, but shows no signs of abatement. Curiously enough, the leaves of the pituri plant, which, as has been mentioned, contain an alkaloid nearly allied to nicotine, are formed into a mass and chewed by the natives of Australia. In smoking, snuffing or chewing, nicotine is absorbed. It has been stated and the 18 274 ORGANIC DRUGS ACTING AFTER ABSORPTION. statement has received an undeservedly wide circulation, that tobacco smoke contains no nicotine but merely the products of its decomposi- tion ; but as a matter of fact, tobacco smoke, whether from cigars or pipes, contains a certain amount of the alkaloid itself, along with pyri- dine and many of its compounds. The amount of nicotine in tobacco smoke cannot be definitely stated, as it depends on the kind of tobacco, as well as on the way in which it is inhaled ; but only a small propor- tion of that contained in tobacco passes over in the smoke. In snuff the nicotine is generally small in amount, while in chewing tobacco there is generally a varying amount of foreign matter, such as molasses. The enjoyment derived from the use of tobacco has never been ex- plained, and it is not even proved that nicotine is essential to the pleasurable results ; consideration of the pharmacological effects of nicotine gives no clue, for these are of the opposite nature. It has been suggested that smoking gives repose and thereby improves intel- lectual work, but this is denied 'by many habitual smokers. It has also been stated and denied that the mental energy is reduced by the use of tobacco, and an attempt has been made to demonstrate this by measuring the amount of work done with and without tobacco ; but investigators are not agreed on the results, which probably depend largely upon the individual. One fact is certain, that the tobacco habit cannot be compared with the use of such drugs as morphine, cocaine, or alcohol, for it is not taken with the purpose of producing stimulation or depression of the central nervous system, and it seems doubtful whether the nicotine ordinarily absorbed really has any action whatso- ever. Perhaps the local effects on the mouth, nose and throat play a larger part in the effects of tobacco than is generally recognized. A certain amount of rhythmic movement demanding no exertion seems in itself to have a soothing, pleasure-giving effect, for it is otherwise impossible to explain the satisfaction enjoyed by many in chewing tasteless objects, such as gum or straws. A curious fact which tends to show that tobacco smoking is not carried on for the sake of the nicotine absorbed is that the pleasure derived from a pipe or cigar is abolished for many persons if the smoke is not seen, as when it is smoked in the dark. Most people may indulge in the moderate use of tobacco for many years with perfect impunity, but its excessive use is followed in many individuals by a number of symptoms, some of them trivial, others indicating grave changes in important organs. One of the commonest effects of overindulgence in tobacco is a chronic inflammation of the throat and upper parts of the respiratory passages, leading to hoarseness and excessive secretion of the mucous glands. This is explained by the constant application to the throat of an irri- tant, alkaline vapor, and is probably not due to the specific action of nicotine. A similar irritated condition of the tongue is frequently met with, more especially when the hot vapor is directed especially on one part, as in pipe smoking, and it is sometimes stated that the constant irritation thus produced renders the tongue and lip more liable to can- NICOTINE AND LOBELINE. 275 cerous disease. -Dyspepsia, want of appetite, and consequent loss of flesh may also be explained by the local irritation produced by the nicotine swallowed in the saliva. A common result of the abuse of tobacco is palpitation and irregularity of the heart, which has been attributed to changes in the inhibitory mechanism. Another import- ant symptom is dimness of vision, especially for colors, and imperfect accommodation, which may go on to complete blindness in one or both eyes. In early cases the retina often appears pale, and if the condition persists, atrophy of the optic nerve may result, probably following on degenerative changes in the ganglion cells of the macular region of the retina. The hearing is said to be affected by excessive smoking, but the symptoms are indistinct and variable. Nervous symptoms such as tremor, exaggeration of the reflexes, headache and giddiness are some- times developed in workmen in tobacco factories, but they do not seem to be induced by smoking or chewing tobacco, though depression, muscu- lar weakness and giddiness are sometimes complained of. In the great majority of cases of chronic tobacco poisoning, the symptoms disappear on abandoning the habit, or even on restricting the daily consump- tion. A series of subjective and even objective symptoms are said to be induced in neurotic subjects by the sudden withdrawal of tobacco. Esser has recently stated that chronic nicotine poisoning in animals induced marked disturbance of the heart, and that degeneration of the vagus fibres are recognizable histologically ; changes have also been found in the nerve cells of the spinal cord and sympathetic ganglia similar to those described under chronic alcoholic poisoning. BIBLIOGRAPHY. Langley and Dickinson. (Journ. of Phys., xi., p. 265), give all the more important experimental literature up to 1890. Langley, Langley and Sherrington, Langley and Anderson. JOUIM. of Phys., xii., xiii., xv., and xxvii., p. 224. Wertheimer et Colas. Archiv de Physiol. (5), iii., 1891, p. 341. Bayliss and Starling. Journ. of Phys., xxiv., p. 99. Hatcher. Amer. Journ. of Phys., xi., p. 17. Dixon and Brodie. Journ. of Phys., xxix., p. 168. Esser. Arch. f. exp. Path. u. Pharm, xlix., p. 190. Greenwood. Journ. of Phys., xi., p. 573. (Action on Li vertebrates.) Moore and Row. Journ. of Phys., xxii., p. 273. Winterberg. Arch. f. exp. Path. u. Phann., xliii., p. 400. Habermann. Ztschr. f. physiol. Chem., xxxiii., p. 55. Beyer. Johns Hopkins Hospital Reports, ix., p. 111. Birch-Hirschfeld. Arch. f. Ophthalmologie, liii., p. 79. Lobeline. Lobeline (C 18 H 23 NO 2 ), the alkaloid of Lobelia inflata or Indian Tobacco, possesses almost exactly the same action as nicotine (Edmunds). PREPARATIONS. Lobelia (U. S. P., B. P.), the leaves and tops of Lobelia inflata, U. S. P., the dried herb, B. P. Fluidextractum Lobelia (U. S. P.), 0.06-0.3 c.c. (l-5mins.). Tinctura Lobelia (U. S. P.), 0.6-4 c.c. (10-60 mins.). Tinctura Lobelias ^Etherea (B. P.), 515 mins. 276 ORGANIC DRUGS ACTING AFTER ABSORPTION. Therapeutic Uses. Lobelia was formerly used as an emetic, but is exceed- ingly depressant and unreliable, and if vomiting does not occur is liable to give rise to the most alarming symptoms of poisoning. The only condition in which it is now used at all is spasmodic asthma, which appears to arise from parox- ysmal contraction of the bronchial muscles. Its action certainly supports this use of the plant, but perhaps it aids in these conditions as much by the increased secretion of the mucous membranes owing to the nausea as through its action on the motor nerves of the bronchial muscles. Its effects must be carefully watched, as the preparations seem to vary in strength, and numerous alarming symptoms and even fatal results have followed its use. BlBLIOGKAPHY. Oil. Phil. Med. Times, vi., p. 121, 1875. Ronnberg. Inaug. Diss., Kostock, 1880. Dreser. Arch. f. exp. Path. u. Pharm., xxvi., p. 237. C. W. Edmunds. Amer. Journ. of Phys., xi., p. 79. XII. THE ATROPINE SERIES. The atropine series contains a number of very closely allied alka- loids, of which the chief are Atropine, Hyoscyamine and Hyoscine or Scopolamine. They are found in several plants of the Solanacese order, and in most cases several of them occur together. Atropine may be broken up by the action of alkalies into an alka- loid, Tropine, and Tropic Acid. The former is a pyridine compound very closely allied to Ecgonine (see cocaine) as may be seen by its structural formula, while the latter is an aromatic acid. Atropine. Tropine radicle. Tropic acid radicle. CH 2 CH CH a N(CH 3 )CHO-CO CH C 6 H 5 CH 2 CH CH 2 CH 2 OH Atropine and hyoscyamine are isomers, and in fact atropine has recently been shown to be racemic hyoscyamine. That is, atropine is a loose combination of hyoscyamine with another isomeric body, dextro-hyoscyamine, which differs from the ordinary or Isevo-hyoscy- amine in the direction in which it rotates a ray of polarized light. The combination of these two hyoscyamines to form atropine exists only in the solid state ; as soon as atropine is dissolved it separates into equal quantities of dextro- and laevo-hyoscyamirie. The action of atropine is thus compounded of the action of these two bodies, which differ very greatly in their pharmacological effects, although they are almost identical in their reactions to chemical reagents. Hyos- cyamine is very readily changed to atropine, and this generally occurs to a large extent in the process of extraction from the plants. Scopolamine (hyoscine) was formerly supposed to be another isomer of atropine, but has lately been shown to differ slightly in its formula, which is C 17 H 21 NO 4 . It is very closely allied to atropine, and is decomposed into tropic acid and Scopoline (Oscine), which was formerly ATROPINE SERIES. 277 supposed to be isomeric with tropine, but has been shown to differ from it in the number of hydrogen and oxygen atoms. A number of other alkaloids have been described in different plants, generally associated with one or more of those already mentioned. But on examination these have generally proved to be mixtures of atropine, hyoscyamine and hyos- cine. Thus the Duboisine of Duboisia myoporoides, the Mandragorine of Man- dragora (Mandrake) and the Daturine of Datura stramonium have all failed to maintain their position as new bases and have proved to be mixtures of the established alkaloids in varying proportions. Atropamine, a new alkaloid found by Hesse in some species of Belladonna, diners slightly in formula from atro- pine, from which it may be formed by the application of heat ; it is decomposed into a substance which is isomeric with tropine, but which differs from it in some respects and which has been called fi-lropine. Atropamine is isomeric but not identical with Belladonnine, which is a compound of yet another isomer of tropine, bellatropine. Pseudo- hyoscyamine is said to differ from atropine and hyoscyamine in some of its chemical relations, but has not been the subject of much work as yet. Atroscine is isomeric with scopolamine, and the same rela- tion appears to exist between them as between atropine and hyoscyamine. After atropine had been found to be a compound of tropine and tropic acid, a number of other acids were attached to tropine in the same way as tropic acid. These artificial alkaloids are known as Tro- peines, and in action resemble atropine in some points while differing from it in others. Further study of the action of these tropeines is exceedingly desirable, and promises to be of considerable value in practical therapeutics. The only artificial tropeine which has as yet been used in medicine is the compound of tropeine and oxytoluic acid known as Homatropine. Scopoleines have been formed by substituting other acids for the tropic acid of scopolamine, but none of them has proved of value in therapeutics as yet. It must be understood that the combination of tropine and its allies with tropic acid does not partake in any way of the nature of the com- bination of an ordinary alkaloid, such as morphine, with an acid. The bond is the much closer one seen in the compound ethers, and the resulting substance is alkaline and combines with acids to form salts exactly as other alkaloids do. The chief plants containing these alkaloids are the following : Atropa Belladonna (Deadly nightshade), containing varying quantities of hyoscyamine and atropine, 1 hyoscine, and sometimes atropamine and belladonnine. Hyoscyamus niger (Henbane), containing hyoscyamine and hyoscine, with smaller quantities of atropine. Datura Stramonium (Thornapple), containing atropine, hyoscyamine, and some hyoscine. Of less importance are : Duboisia myoporoides, containing hyoscine and hyoscyamine, together with pseudo-hyoscyamine and other alkaloids. Another species of Duboisia contains piturine, an alkaloid nearly allied to nicotine. Scopola atropoides, containing hyoscyamine and hyoscine, and perhaps small quantities of atropine. 1 The relative proportion of atropine and hyoscyamine in all these plants is not known, as hyoscyamine is very often changed to atropine in the process of extraction. 278 ORGANIC DRUGS ACTING AFTER ABSORPTION, Mandragora autumnalis, or Atropa mandragora (Mandrake), containing hyos- cyamine with traces of other alkaloids. A number of other Solanacese e. g., tobacco and potato leaves, are said to contain small quantities of one or other of these alkaloids but the quantity present here is too small to be of any importance. A ptomaine formed by the decomposition of fish and meat and known as ptomatropine also produces symptoms closely resembling those of atropine poisoning, but has not been isolated as yet. These alkaloids all resemble each other closely in the effects pro- duced by them in animals. Some differences in the symptoms exist, however, and the action of atropine alone will first be described and later the points in which that of hyoscyamine and of hyoscine differ from it. Atropine acts as a stimulant to the central nervous system and paralyzes the terminations of a number of nerves, more especially those that supply involuntary muscle, secretory glands and the heart. Symptoms. In man and the higher animals small toxic doses cause dryness of the skin and throat, thirst, difficulty in swallowing and hoarseness in speaking. There is often nausea and in some cases vomiting, headache and giddiness ; the pupils are wider than normal and the sight may be indistinct, especially for near objects. The res- piration and pulse are quickened, or the latter may at first be some- what slowed. A symptom that is often present, though by no means invariably so, is redness of the skin, more especially of the head and neck ; the conjunctiva may also be congested. After larger doses the same symptoms are observed, but are soon followed by others of graver import. The patient can no longer swallow, although suffering from intense thirst, the heart is generally extremely rapid, speech is difficult and hoarse, and the pupils are dilated until the iris almost dis- appears. Restlessness and garrulity point to an increase in the irri- tability of the brain ; the patient at first talks in a perfectly normal way but soon becomes confused, begins a sentence and does not finish it, often bursts into laughter or tears, and in short becomes delirious and eventually maniacal. Often marked tremor of different muscles may be observed, and eventually convulsions set in and may be the cause of death through the failure of the respiration. As a general rule, however, the stage of excitement passes into one of depression, the patient sinks into a sleep, which deepens into stupor and coma, the respiration and heart become slow, weak and irregular, and death eventually occurs from asphyxia. In the frog the injection of small quantities of atropine is followed by a stage of increased reflex excitability, exactly resembling that seen under strychnine. It is generally of short duration, however, and is followed by a stage in which the frog lies motionless and does not react to stim- ulation in any way. After a variable time, sometimes a few hours, oftener several days, a return of the first symptom occurs, the reflex being much exaggerated and the tonic convulsions described under strychnine being generally developed. This stage slowly passes off and the animal again becomes normal. ATROPINE SERIES. 279 Action. These symptoms both in mammals and amphibians indi- cate stimulation of the Central Nervous System followed by depression. Those observed in man sometimes resemble those seen in the excite- ment stage of alcoholic poisoning, and it has been suggested that in both the cause is rather a lessening of the control normally exercised by the higher powers over the lower motor areas than a true stimula- tion of the latter. But this is shown to be incorrect by the fact that in atropine poisoning the motor area is more easily stimulated by the electric current than normally. The stimulant action of atro- pine is also seen in the increased reflex response to irritation of the skin, as well as in the augmented activity of the centres in the medulla. The nervous symptoms under atropine, therefore, arise from true stim- ulation of the central nervous system, but they are wholly different 1 from those produced by strychnine, because the latter acts more espe- cially on the lower parts of the nervous axis, while atropine acts more strongly on the higher divisions. The most marked symptoms of strychnine poisoning arise from the spinal cord and medulla oblongata, and consist in increased reflex movements and convulsions, while those caused by atropine are rather to be referred to the brain, and consist in increased coordinated movements, such as talking and delirium, the exaggerated reflex being of minor importance. In the frog the same effects are produced by each, because the higher parts of the central nervous system being less developed than in the mammals, the first symptoms produced are those arising from the cord. Atropine differs from caffeine, on the other hand, in its effect on the brain, for under the latter the psychical functions are those affected^ first of all. It would seem probable, then, that each of these three j stimulates the whole of the central nervous system more or less, but: ; that while strychnine acts more strongly on the lojvyer^di visions, the? spinal cord and medulla, and oaffei ne, on the highest functions^ the. _4>sychical, atrooine ^occupies a midway position, and exercises its chiefs action on the motor divisions of the brain. These are rendered so ex- citable that the controlling areas can no longer keep them in check, and an increase in movement occurs somewhat resembling that seen when the controlling areas are paralyzed by alcohol. The stimulant action spreads downwards when large quantities have been absorbed, and involves the medulla oblongata and spinal cord, so that symptoms resembling those seen in strychnine poisoning may make their ap- pearance. After the stimulation has lasted some time, depression sets in and may go on to complete paralysis of the central nervous system. This is fatal to mammals through cessation of the respiration, but in the amphibia the paralysis may pass off after some time as the poison is excreted, and the stage of stimulation is renewed. Even during the stimulation stage some symptoms of depression are to be made out, exactly as has been described under strychnine. The peripheral action of atropine involves a number of secretory glands, the organs containing unstriped muscular tissue and the heart. Most of the Secretions are decreased by the application of atropine 280 ORGANIC DRUGS ACTING AFTER ABSORPTION. salivary, mucous, milk and sweat. This is due not to any action upon the secretory cells, but to paralysis of some of the nerve ends. It has been investigated most carefully in the salivary glands, but enough work has been done on the others to show that the process is the same in all. The secretion of saliva in the normal animal seems to occur only when impulses reach the gland cells by one of two paths through the chorda tympani, or through the cervical sympathetic fibres. If the chorda tympani be divided and put on electrodes and a canula be passed into Wharton's duct, a rapid flow occurs through it on stimulation of the nerve, which ceases or is very much diminished on stopping the stimulation. If now atropine be injected, stimulation causes no increase in the secretion and atropine, therefore, seems to paralyze some part of the peripheral secretory apparatus. The chorda tympani passes through ganglion cells on its way to the gland cells, and the impulses might be hindered in their passage through these, as actually occurs under the action of some drugs. (See Nico- tine.) But this is not the explanation of the inefficiency of chorda stimulation, as is shown by the fact that if the electrodes be pushed into the hilus of the gland so as to stimulate the nerve fibres beyond the ganglia no secretion follows. Another explanation would be that the gland cells themselves are paralyzed by atropine, but this is shown not to be the case, for on stimulating the sympathetic which supplies the same cells as the chorda tympani, the usual secretion follows. The site of action of atropine, therefore, seems to lie between the ganglion cells on the course of the chorda tympani and the secretory cells, that is, the point of attack is the terminations of the nerve fibres in the gland cells. The action is limited to certain definite terminations, for it has been noted already that the sympathetic secretory fibres are not par- alyzed, and it was discovered by Heidenhain that not all the fibres of the chorda tympani are acted on by atropine. On stimulation of this nerve in the unpoisoned animal, besides the increased secretion, a red- ness and swelling of the gland is noticed, its temperature rises, and the blood escapes from the veins in much larger quantity than usual and in spurts as if from an artery. This is due to the dilation of- the arterioles of the gland from the stimulation of vaso-dilator fibres which run along with the secretory fibres in the chorda tympani. These fibres are not paralyzed by an injection of atropine, for on stim- ulation of the chorda afterwards the same symptoms are produced as before, save that no secretion occurs. Atropine then seems to select the terminations of the secretory fibres of the chorda tympani for paralysis and to leave all others unaffected. The secretion of saliva seems to occur generally only on the arrival of impulses by way of the chorda tympani, so that on the paralysis of its terminations the secre- tion ceases entirely. In the same way the other glands of the mouth, throat, nose and res- piratory passages cease secreting after atropine, and the eifect is the char- acteristic dryness of the mouth, the hoarseness of the voice, and the thirst and difficulty in swallowing complained of after its administration. ATROPINE SERIES. 281 The secretion of the gastric juice has recently been shown to be diminished or entirely arrested by atropine, which paralyzes the termi- nations of the secretory fibres of the pneumogastric nerve in the stomach. The hydrochloric acid of the secretion is more reduced than either the pepsin or the fluid as a whole. The pancreatic secretion may be induced either by nervous impulses reaching it by the fibres of the pneumogastric, or by the secretion formed in the intestinal epithelium being carried to it by the bloodvessels ; atropine paralyzes the termina- tions of the pneumogastric so that no secretion arises from its stimulation, but the intestinal secretion acts directly on the pancreatic cells so that the gland continues to respond to its presence. The bile is also said to be somewhat lessened by atropine. The production of sugar from the gly- cogen of the liver has been recently shown to be controlled by branches \ \ of the coeliac plexus, but these have no effect after atropine, so that the terminations of the nerves in the liver cells seem to be paralyzed also. } The same paralysis is produced in the terminations of the nerves in the siueat glands. Stimulation of the sciatic nerve as a general rule produces perspiration in the foot of the cat and dog, but after atropine this effect is absent, because the impulses cannot reach the cells through the paralyzed terminations, and the skin therefore becomes dry and hot. The secretion of milk bears the same relation to that of per- spiration as that of the pancreatic juice does to the saliva ; it is increased by stimuli from the central nervous system, but at the same time the mammary gland continues to secrete after all its nerves have been divided. Atropine therefore lessens the secretion by para- lyzing its nerves, but does not stop it altogether. The solids of the milk seem rather increased than diminished by the drug. The kidney is not controlled so directly by nervous influences as the glands hitherto discussed, and atropine causes little or no change in the amount of urine except what is probably the indirect result of the arrest of the other secretions. The secretion of lymph is not altered by atro- pine, so that it is probably not controlled by nerves in the same way as the true secretions. All Organs Containing Unstriped Muscle (apart from the arterial wall) seem to be altered by atropine. Thus the movements of the stomach, intestine, bladder, uterus, spleen, thoracic duct, and of the pupil and oesophagus (except in animals, in which these consist of striped muscle) are lessened by atropine. Atropine has generally a sedative effect on the movements of the stomach and intestine, though vomiting is not infrequently observed in cases of poisoning, and less often free evacuation of the contents of the bowel. The increased movement induced by ordinary doses of -: the purgatives is not arrested, but the griping pains resulting from ] ; large doses or from the more violent purgatives are absent or less,: marked if atropine is given along with them. Similarly, the violent peristaltic and tetanic contractions seen after such poisons as nicotine and muscarine are prevented by the preliminary injection of atropine. These results were formerly explained by supposing that atropine para- 282 ORGANIC DRUGS ACTING AFTER ABSORPTION. lyzed the terminations of the extrinsic motor nerve of the bowel in the same way as it paralyzes the terminations of the chorda tympani. But Bayliss and Starling and Dixon have recently shown that atropine does not alter the effect of stimulation of the vagus, the motor nerve of the intestine and stomach, nor of that of the splanchnic, the inhibi- tory nerve. The fact that it antagonizes the excessive movement after these poisons cannot be attributed to action on the terminations of these nerves, therefore, and no other explanation of the unquestion- able effect of atropine on the stomach and bowel has been vouchsafed. It appears possible that atropine acts on some still unknown nerve terminations, and that the violent movements which it arrests arise from stimulation of a mechanism which is distinct from that presiding over the ordinary peristalsis. Atropine exercises the same sedative effect on the movements of other organs as on those of the bowel. Thus, the spleen, uterus, bladder, and the bronchial muscles seem less liable to contraction after its use. In regard to its action on the two first but little is known, but Dreser has shown that the stimulation of the pneumogastric does not cause con- traction of the bronchial muscle after atropine, while in the unpoisoned animal it has this effect. In regard to the bladder it has been observed frequently in cases of poisoning that the urine is ejected soon after the ingestion of the poison, and subsequently there is a desire to micturate without the ability to do so. The preliminary contraction of the blad- der would seem analogous to that of the intestine, and the subsequent inability to empty it to the diminution of the peristalsis. The rhyth- mical contractions of the ureters are said to be accelerated by small doses, but to be slowed and arrested by larger amounts. -The terminations of the nerves in the unstriped muscle of the oesophagus seem to be affected in the same way as in that of the intes- tine. A curious contrast has been noted by Luchsinger in the behavior of the oesophagus in rabbits and cats, in the former of which the mus- cle is striated, while in the latter the upper part is striated, the lower is unstriated. Atropine, he found, paralyzes the vagus terminations in those parts which are unstriped, while leaving unaffected those in the striped fibres. Exactly the opposite occurs after curara, which para- lyzes the nerve supply of the striped muscle, while leaving the unstriped active. Here, again, is evidence of the selective power of these poisons and of the difference in the chemical composition of nearly related structures. It is possible that the difficulty in swallowing, which is so well marked in cases of poisoning by atropine, may be due in part to the paralysis of the motor nerve ends, but it is generally attributed to the absence of the mucous secretion and consequent dryness of the pas- sages. The dilatation of the pupil by atropine has been the subject of a very large number of researches both by physiologists and by practical ophthalmologists. It occurs on internal administration as well as on the application of minute quantities locally, and is due to paralysis of ATROPINE SERIES. 283 the terminations of the motor nerve in the circular muscle of the iris. This is shown by the fact that stimulation of the motor oculi nerve or of the sympathetic neuron running from the ciliary ganglion is without effect, as well as that the dilatation may be produced by atropine in the excised eye. This limits the paralysis to the periphery, and that the muscle is not acted on is shown by its reacting to electrical stimu- lation. The local nature of the action may be further shown by care- fully applying a minute quantity of the drug to one side of the cornea, when dilatation of one half or less of the pupil occurs, the rest remain- ing contracted. The motor oculi (Fig. 26) constantly transmits im- pulses through the ciliary nerves to the sphincter muscle of the iris and keeps the pupil moderately contracted, and when these impulses can no longer reach the iris owing to the paraJysis of the nerve ends, the FIG. 26. Diagram of the innervation of the iris. P, a fibre of the motor oculi passing from the brain to the ciliary ganglion (JV) in which it terminates around a nerve cell, which sends an axis cylinder to ter- minate M, in the circular fibres of the iris. R, a spinal nerve fibre issuing from the lower cervical cord, running through the stellate and inferior cervical ganglia and terminating around a ganglion cell in the superior cervical ganglion, G. The axis cylinder from this nerve cell runs to the iris (pass- ing the ciliary ganglion) and terminates, C, on the radiating fibres. M indicates the terminations of the nerve fibre in the circular fibres, and is the point acted on by atropine and muscarine. NN' the ganglion cells, is the seat of action of nicotine. C, the terminations in the dilator fibres, that of cocaine. sphincter relaxes and the pupil dilates. The muscle itself does npi seem to be affected by the ordinary application of atropine, but if strong solutions be continuously applied, its fibres may be paralyzed by it as by many other drugs. The action in paralyzing^ the nerve end is universally accepted now, although it was formerly disputed. 284 ORGANIC DRUGS ACTING AFTE& ABSORPTION. A farther question is whether this is the only effect of atropine on the pupil, or whether the terminations of the dilating sympathetic fibres are not stimulated at the same time, and this cannot as yet be said to be generally agreed upon, although there is very strong evidence against the latter view. Its advocates have generally ignored the fact that the constrictor muscle is constantly opposed by dilator fibres, and that when the former is thrown out of activity by the paralysis of the terminations of the motor oculi, the radiat- ing fibres cause an active dilatation without any stimulation of the nerve ends being necessary. If, however, the radiating muscular fibres be separated from their innervating centre by section of the cervical sympathetic nerve in the neck, they also cease to contract and there is no active dilatation, so that atropine causes less widening of the pupil than it would if impulses continued to reach the radiating muscle. After the application of atropine to the eye, the iris often relaxes with sufficient force to tear weak adhesions to the lens, and this has also been held to indicate that the dilator fibres are stimulated, for it is unlikely that the mere passive relaxation of the iris could rupture an attachment. Similarly, if the iris be attached at two points to the lens, atropine causes a bow-shaped dilatation between them, the concavity being directed inward, whereas if the dilatation were purely passive the part between the points of attachment would probably be loose and wrinkled. The dilatation is unquestionably an active movement, accomplished by the contraction of the radiating muscular fibres, but these are not put in motion by stimulation of the terminations of the fibres in the radiating muscles of the iris, but by the normal impulses descending from the central nervous system, which aiter atropine are not counterbalanced by impulses reaching the circular fibres. In short, the evidence goes to prove that atropine dilates the pupil \ by paralyzing the terminations of the nerves in the circular muscle. This leaves the radiating fibres unopposed, and they therefore draw Back the edge of the iris. The terminations of the nerves in the radi- * ating muscle fibres do not seem to be affected by atropine. The dilatation of the pupil effected by atropine is not quite maximal, v for stimulation of the cervical sympathetic trunk generally increases it, though but slightly. It differs considerably in different animals, be- ing more complete in man, the dog, and the cat than in the rabbit, entirely absent in birds and reptiles and elicited with difficulty in the frog. In birds and reptiles the iris consists of striped muscle fibres, and accordingly atropine has no action on the nerve terminations. In the rabbit and in man the dilatation is sometimes preceded by a slight contraction due, it is believed, to an irritant preparation setting up a reflex from the conjunctival sensory nerves. When complete dila- tation is attained, the pupil ceases to contract in bright light, as the impulses descending from the central nervous system are prevented from reaching the muscle, although the rest of the reflex arc is intact. According to several observers the pupil dilated by atropine contracts during narcosis from chloroform or chloral, but this statement requires further confirmation. Besides the dilatation of the pupil, a further result of the applica- tion of atropine to the eye is the paralysis of the accommodation. Near objects are no longer seen clearly, while distant ones are as distinct as formerly or may be even more distinct in some eyes. The action is here again on the terminations of the motor nerve, in this case in the ciliary muscle. On local application the relaxation of the lens occurs ATROPINE SERIES. 285 later, and disappears earlier than the dilatation of the pupil, and larger quantities are required to produce it.. The intraocular pressure undergoes a considerable augmentation after the local application of atropine as well as when it is applied through the general circulation. This seems to be due to the dilatation of the pupil, although some writers seem to believe that atropine has also a special action on the intraocular fluids. The increase in the intra- ocular pressure has been demonstrated in animals through the move- ments of a manometer communicating with the vitreous humor, and is a well-known result of the application of atropine in ophthalmology. It may, perhaps, explain the pain and aching in the eye and the head- ache complained of in some cases of poisoning, while in others these may be due to bright light falling on the retina, which is unprotected by the iris. Atropine paralyzes the Inhibitory Terminations of the Vagus in the Heart, and stimulation of this nerve therefore causes no changes in the pulse after its administration. A number of other drugs also remove the inhibitory power of the vagus, but act on a different part of the nerve, namely, on the ganglia. That atropine does not act here but on the terminations, has been shown by a number of observations. FIG. 27. Tracings of the ventricle (lower) and auricle (upper) of the dog's heart. During systole the levers move upwards ; during diastole, downwards. At A, the heart is normal ; at B, the inhibitory fibres were stimulated electrically, and this was continued throughout the tracing. The ventricular rhythm became slow and irregular, while the auricle stood still in diastole. At C, atropine sulphate was injected into a vein, and at D the effects of the inhibition began to pass off, although the stimula- tion was continued. Thus, in the normal frog's heart, and even after paralysis of the gan- glia on the course of the vagus, electrical stimulation of the venous sinus causes slowing and standstill of the heart, because the stimulus reaches the vagus beyond the paralyzed ganglia (Fig. 24, p. 267) ; but after atropine, no slowing follows stimulation of the sinus. Again, several drugs stimulate the ends of the vagus in the heart and act on parts in which no ganglia exist, but these drugs have no effect whatever after atropine. Small quantities of atropine have no further action on the heart than the paralysis of the inhibitory nerve ends. The ter- minations of the accelerator nerve are unaffected, exactly as the ter- minations of the sympathetic in the salivary glands, and the heart mus- cle is neither stimulated nor depressed. The heart is therefore placed 286 ORGANIC DRUGS ACTING AFTER ABSORPTION. in the same position as if the vagus were divided in the neck, and, ac- cordingly, is accelerated in some animals, while in others the rhythm is unchanged. In the dog there is a marked quickening of the heart after atropine, because normally impulses are constantly transmitted from the inhibitory centre in the medulla, and these prevent the heart from beating as rapidly as it would if freed from the nervous control. In the cat the " tone " of the vagus is less, and the changes produced by atropine are correspondingly smaller, while in the rabbit and frog there is generally no inhibitory retardation of the heart, and atropine therefore produces little change. In man the eifects vary considerably with the age of the patient. The inhibitory fibres seem almost inactive at birth, but their tone increases with age up to 25-35 years, and from this time lessens again and is very slight in old age. Atropine does not quicken the heart in the newborn child, but up to about 30 the accel- eration increases with the age, and from this point onwards it lessens again until the heart is accelerated by only 45 beats per minute in patients between 80-90 years. Along with the acceleration of the pulse the other eifects of vagus section are also produced increase in the extent of systole, decrease in the diastole and augmentation of the output of the heart per minute. Stimulation of the vagus causes no retardation of the pulse after atropine, but on the contrary, is not infrequently followed by acceleration from the presence of accelerator fibres which are not affected by atropine. Large quantities of atropine, besides paralyzing the vagus, weaken and depress the heart muscle and the contractions consequently become slower and weaker and the output of the heart is less than normal. Hedbom states that large quantities accelerate the coronary circulation in mammals and increase the amplitude of the contractions. He is inclined to regard the latter alteration as due in part to the dilatation of the coronary vessels, in part to a direct action on the heart muscle. The peripheral action of atropine hitherto discussed is due to its para- lyzing the terminations of a number of nerves in small doses and to its paralyzing the muscle or gland cells when administered in very large quan- tities. These facts are generally accepted as true, but a number of further effects have been disputed and may now be shortly discussed. It is not seldom stated that atropine, in addition to paralyzing the vagus ends, stimulates the heart muscle and thereby quickens its rhythm. This assertion is somewhat difficult to disprove, but none of the alleged facts brought forward to support it have stood closer investigation. The error generally arose from the belief that atropine acted on the ganglia and not on the nerve ends or from the use of impure and irritant preparations, and all the phenomena on which it was based may be explained by the more modern theory that the ganglia on the course of the inhibitory nerve fibres are left intact by atropine, while the terminations of the nerve are paralyzed. A further question is whether the nerve ends are paralyzed at once or whether they undergo a short stimulation first. In favor of the latter theory several facts may be mentioned, as that the heart in mammals is often first slowed and then quickened by atropine. This might indicate stimu- lation of the nerve ends, but seems due rather to the inhibitory centre in the medulla being stimulated before the terminations are paralyzed. This stimulation of the centre slows the heart until the impulses sent out from it are prevented from reaching the organ by paralysis of the nerve ends. The increase in the intestinal movements, which occurs immediately after the ATROPINE SERIES. 287 injection of atropine, might also be cited as proof of the preliminary stimu- lation of the nerve ends, but may also be explained by the inhibitory terminations being paralyzed earlier than the motor, so that these have a brief period of unrestrained activity. In the eye a short stage of contraction of the pupil not infrequently precedes the dilatation, but it is generally believed to be due to a reflex from the application of an irritant solution to the conjunctiva. Lastly, when atropine is applied to the eye of the cat a considerable secretion of saliva almost always follows for a short time, and this might be held to indicate a stimulation of the terminations of the chorda. It is more likely, however, that it is a reflex secretion from the bitter taste of the alkaloid which has escaped through the lachrymal duct into the back of the throat. Several alkaloids stimulate the same peripheral nerve terminations as atropine paralyzes, and the interaction of the two groups is of con- siderable importance. It is more profitably discussed after the general action of these poisons has been learned, and will be taken up at that point (see rnuscarine, pilocarpine, and physostigmine ; compare also nicotine and the curara and coniine series). The voluntary Muscles are not directly affected by atropine. The terminations of the motor Nerves are paralyzed in the frog by large doses, but this has not been elicited in mammals by ordinary meth- ods of experimental investigation. The terminations of the sensory nerves are paralyzed, or at any rate depressed by its local application. Thus when a liniment or ointment containing atropine is applied to the skin, a numbness of the part is produced and the sensation of pain is lessened. The local anaesthetic effect is not elicited by its internal administration, although it is said that the frog may be rendered less sensitive to irritation of the skin if poisoned with atropine. Accord- ing to some recent investigations the sensory terminations are first stimulated and then paralyzed, but the assertion stands in need of con- firmation. Circulation. The effect of atropine on the circulation is somewhat complex, as, besides the action on the heart, that on the central nervous system must be considered.. The heart is sometimes slowed and weak- ened at first, owing to the stimulation of the inhibitory centre in the medulla probably, but is generally quickened from paralysis of the in- hibitory fibres in the heart, and after very large doses is weakened by the direct action on the muscle fibre. The blood-pressure is consider- ably increased by the augmented output of the accelerated heart, and also owing to stimulation of the vaso-constrictor centre in the medulla which cign.tra.cts the arterioles^ in the__abdom en . The constriction of these vessels is accompanied by a dilation of the arterioles of the skin, and perhaps of the brain, from excitation of the vaso-dilator centre, so that the blood tends to flow from the abdominal cavity to the more superficial parts. The dilation of the skin vessels is, however, insuf- ficient to counteract altogether the contraction of those of the abdomen, so that a considerable increase in the arterial tension follows the in- gestion of atropine. The increased pressure is maintained for some time after small doses, while large ones lower it from the action on the heart muscle. The dilation of the skin vessels is more especially 288 ORGANIC DRUGS ACTING AFTER ABSORPTION. seen in the head and neck, and here produces marked flushing and a rash somewhat resembling that of scarlet fever. That it is due to central action is shown by the fact that it is prevented by division of the sympathetic trunk in the neck. The rash usually disappears after a few hours, but is sometimes followed in a day or two by desquama- tion. The circulation always persists after the respiration has ceased, and its failure is not the cause of death therefore. The action of atropine on the Respiration has been the subject of much discussion in recent years. It is sometimes slower at first through some unexplained central action but then becomes quicker, and ac- cording to most observers also deeper, and the amount of air inspired per minute is considerably increased. This is due to stimulation of the respiratory centre, which undergoes the same changes as the rest of the central nervous system. After large doses this quickened breathing is frequently interrupted by convulsive movements, and such an interruption often proves to be final. If it returns, the move- ments become shallower and slower in the stage of depression of the nervous centres, and the failure of the respiration is the cause of death in fatal cases of poisoning. Atropine often induces a marked rise in Temperature, the cause of which cannot be said to be definitely known. According to Ott the dissipation of heat is increased, but the heat formation undergoes- a still greater augmentation. This seems to be independent of the cir- culatory changes and also of the convulsions, and is attributed by him to direct action on the heat centres of the brain. Atropine is Excreted in the urine in small quantities when injected into the dog, but most of it undergoes complete oxidation in the tissues ; in the rabbit this seems to be the fate of the whole of the drug, for none is found in the excretions. 1 Young animals withstand much larger quantities than adults, according to v. Anrep because the brain is less highly developed and the cerebral symptoms are therefore produced less easily. Rabbits may be fed for weeks on belladonna leaves exclu- sively without showing any symptoms of poisoning, while carnivorous animals and man are very much more sensitive to its action. A curious case of poisoning is related in which the defence was made that the alka- loid was taken accidentally through partaking of roast rabbit, the ani- mal's flesh having been saturated with atropine through feeding on bella- donna leaves. It was found that rabbits thus fed might, in fact, con- tain large quantities of atropine and yet show no signs of poisoning. Von Anrep succeeded in developing a certain degree of Tolerance in dogs through repeated administration of atropine, but it was very in- complete. The symptoms arising from the central nervous system were much less evident after a few doses, while those from the heart, pupil and secretory glands persisted after the treatment had been con- tinued for some time. Hyoscyamine is rarely obtainable in pure form, as it is almost always mixed with atropine, into which it changes when kept in solution and 1 Traces have been found in the milk of some animals and also in the foetal blood. ATROPINE SERIES. 289 perhaps even when dry. It paralyzes the peripheral terminations of the same nerves as atropine, but acts almost exactly twice as strongly on them. Its action on the central nervous system in mammals | resembles that of atropine and the fatal dose is the same, but in the frog it has less tendency to cause convulsions. No narcotic influence is exercised on either frogs or mammals ; the belief that it induces sleep is founded on observations in which hyoscine was mixed with the hyoscyamine employed. The action of atropine, as has been stated, is compounded of that of natu- ral or laevorotary hyoscyamine with that of its dextrorotary isomer. The latter does not exist free in nature and possesses only a feeble action on the nerve terminations, while it stimulates the spinal cord of the frog more than either atropine or hyoscyamine. The peripheral action of atropine is thus due to its containing hyoscyamine, and as a grain of atropine contains only half a grain of hyoscyamine the former naturally exercises only half the effect of a grain of hyoscyamine. On the other hand, the half grain of dextrorotary hyoscy- amine in a grain of atropine is almost inert on the nerve terminations, but exer- cises the same effect on the central nervous system as its Ia3vorotary complement. Atropine thus acts on the central nervous system in mammals in the same strength as hyoscyamine, but only half as strongly in the periphery. Scopolamine, or Hyoscine, resembles atropine closely in its peripheral action. The inhibitory terminations in the heart are paralyzed, although the therapeutic dose in man is too small to elicit this effect and the pulse is therefore unaltered in rate or may be slower owing to the hypnotic action. It produces mydriasis and loss of accommoda- tion more quickly than atropine, but for a much shorter time ; pure hyoscine acts about twice as strongly on the nerve terminations as atropine, or about equally strongly with hyoscyamine. The effects on the central nervous system present the greatest divergences from those described under atropine, for the characteristic stimulation is absent in the great majority of cases. As a general rule, scopolamine produces a marked sensation of fatigue and drowsiness, and the patient moves about less and speaks less. Soon an overpowering desire to sleep is felt, and a condition in no way dissimilar to the natural sleep follows. In many cases, however, a short stage of excitement with giddiness, uncertain movements, and difficult and indistinct speech precedes sleep, and occasionally symptoms exactly resembling those produced by atro- piiie follow the administration of hyoscine, especially if large doses are employed. Sleep generally lasts from 5-8 hours, and the patient may then remain in a somnolent condition for several hours longer. As a general rule, after small doses no confusion is complained of on awakening, but dryness of the throat and thirst are often present. Larger doses do not cause deeper sleep but give rise to delirium and excitement resembling those following atropine. In one or two cases collapse has been observed after scopolamine. The vaso-motor and respiratory centres do not seem to be stimulated as by atropine, the blood-pressure falling and the respiration generally becoming slower from the beginning. In the lower mammals scopolamine reduces the excitability of the motor areas as tested by electric shocks, while the reflex excitability in 19 290 ORGANIC DRUGS ACTING AFTER ABSORPTION. the frog is not increased as by atropine. Hyoscine appears to be excreted or destroyed in the tissues much more rapidly than atropine, for its effects last a shorter time. JThe action of hyoscine, then, seems to correspond with that of atro- 1 pine, save that the central nervous system is here depressed, while the i action on the peripheral nerve ends is stronger. It depresses the brain in very smairquantities, J mg. ( T gr.) being generally sufficient to cause sleep. It does not seem to be so dangerous as the others of the series, for a dose of 5 mgs. (^ gr.) has been recovered from in man, and over half a gramme (7J- grs.) administered to a small cat did not kill the animal. A certain degree of tolerance is produced after repeated use, so that the dose has to be increased after a week or two. It must be remarked that the action of hyoscine as a hypnotic differs considerably from that of opium and of the members Tot tne methane series ; it is very much less reliable, and the sleep produced resembles much more nearly natural sleep. This difference has not been explained, but it seems probable that the seat of action differs in all three. The Other Natural Alkaloids have been less carefully examined than the three foregoing ; such mixtures as duboisine of course combine the effects of their constituents. The pseudo-hyoscyamine of Merck seems to be very feebly active, causing dilatation of the pupil on local appli- cation, but having little or no effect when given internally. Among the Artificial Tropeines, only one has received much attention at the hands of either experimental or practical therapeutists. This is Homatropine, a compound of tropine and mandelic acid, which is found to be less poisonous than atropine but to resemble it in the symptoms produced by an overdose. The mydriatic effects pass off much sooner than those produced by the usual solutions of atropine, and are said to appear more rapidly and to be less complete. It was formerly supposed that homatropine caused no increase in the intra- ocular tension, but this has been shown to be erroneous, although it is less active in this direction than atropine. Several other tropeines have been examined by Falck and Gottlieb, who found that they varied a great deal in their action on the lower animals. Many of them produce no paralysis of the oculomotor or the vagus termi- nations, while others act here in the same way as atropine, but differ from it in power. It may be stated that in general the compounds of tropine with the acids of the methane series possess much less of the peripheral atropine action than the others. It was formerly believed that even the compounds with the aromatic acids were devoid of this action unless the acid possessed a hydroxyl group, but this general statement has been shown to be erro- neous by Gottlieb's work. A considerable variation also exists in the effects of the tropeines on the central nervous system, some causing excitement like atropine, while others act as depressants and therefore resemble hyoscine. As has been mentioned, many of the tropeines cause no paralysis of the vagus inhibitory terminations but they often act as stimulants to the frog's heart. Tropine itself is a weakly toxic, basic substance, which in large quantities possesses this cardiac action, but does not paralyze the vagus nor the oculomotor terminations on local application. After the injection of large quantities, dilatation of the pupil has been observed, it is true, but this does not seem to be of the same origin as that produced by atropine. ATROPINE SERIES. 291 Some artificial scopoleines have been examined recently by Schiller, who found that they differed from scopolamine in being devoid of action on the nerve ends in the pupil and heart and on the salivary secretion. They possess a certain stimulant effect on the heart muscle like some of the artificial tropeines, and all produce more or less depression of the central nervous system and narcosis. METHYLATROPINE (Eumydrin) is said to possess the peripheral action of atro- pine without its effects on the central nervous system. Its effects on the pupil in 1 per cent, solution appear sooner and are less lasting than those of atropine. The action of the Crude Drugs is very similar to that of the active principles already discussed. The peripheral action of all of them is v therefore almost identical in kind, though varying in degree. In con- \ \sidering their effects on the central nervous system it must be remem- I Jbered that those containing much atropine are more stimulant, those | 'with hyoscine more sedative. In belladonna preparations the quantity of hyoscyamine varies a good deal, and it is said that no atropine is present in the fresh plant, but that during the various processes of ex- traction some or all of the original hyoscyamine becomes changed to atropine ; the relative proportion of these two poisons probably varies in different preparations, therefore. In hyoscyamus and scopola the presence of scopolamine produces a much more narcotic effect than is obtained from belladonna, while datura is generally said to be less seda- tive than the former, but less stimulant than the latter. Duboisia also seems rather sedative than stimulant, but its action and that of its so-called alkaloid must vary considerably, since the latter consists at one time of hyoscine, at another of hyoscyamine. Mandragora con- taining hyoscyamine and hyoscine probably resembles hyoscyamus in its effects. PREPARATIONS. U. S. F. Belladonnae Folia, the leaves of Atropa Belladonna. EXTRACTUM BELLADONNA FOLIORUM, 0.005-0.03 G. ( T V~2 gr.)- TINCTURA BELLADONNA FOLIORUM, 0.3-1 c.c (5-15 mins.). Utiguentum Belladonnce. EMPLASTRUM BELLADONNA. Belladonnas Radix, the root of Atropa Belladonna. Fluidextractum Belladonnce Radicis, 0.05-0.1 c.c. (1-2 rnins.). LINIMENTUM BELLADONNA, containing camphor. Hyoscyamus, the leaves of Hyoscyamus niger, henbane. EXTRACTUM HYOSCYAMI, 0.03-0.2 G. (-3grs.), Fluidextractum Hyoscyami, 0.3-1 c.c. (5-15 mins.). TINCTURA HYOSCYAMI, 1-4 c.c. (15-60 mins. ). STRAMONIUM, the dried leaves of Datura Stramonium. Extractum Stramonii, 0.01 G. ( gr.). Fluidextractum Stramonii, 0.5 c.c. (1 min.). Tinctura Stramonii, 0.5 c.c. (8 mins.). Unguentum Stramonii. SCOPOLA, the dried rhizome of Scopola carniolica. Extractum Scopolce, 0.01 G. ( gr.). Fluidextractum Scopolce, 0.05 c.c. (1 min.). B. P. Belladonnas Folia, the fresh leaves and branches of Atropa Bella- donna. Extractum Belladonnce Viride, | 1 gr. Succus Belladonnce, 5-15 mins. Belladonnas Radix, the root of Atropa Belladonna. EXTRACTUM BELLADONNCE ALCOHOLICUM (1 per cent, of alkaloids), ^-1 gr. 292 ORGANIC DRUGS ACTING AFTER ABSORPTION. EXTRACTUM BELLADONNA ALCOHOLICUM (1 per cent, of alkaloids), -1 gr. Extractum Belladonna Liquidum (f per cent, of alkaloids), -1 min. TINCTURA BELLADONNA (^ per cent, alkaloids), 5-15 mins. LINIMENTUM BELLADONNA. Unguentum Belladonna. EMPLASTRUM BELLADONNA. Suppositoria Belladonnse, each containing -fa g r - of alkaloids. Hyoscyami Folia, the fresh leaves, flowers and branches of Hyoscyamus niger, henbane. EXTRACTUM HYOSCYAMI VIRIDE, 2-8 grs. Tinctura Hyoscyami, -1 fl. dr. Succus Hyoscyami, -1 fl. dr. Stramonii Folia, the dried leaves of Datura Stramonium. Tinctura Stramonii, 5-15 mins. Stramonii Semina, the seeds of Datura Stramonium. Extractum Stramonii, \-\. gr. Alkaloids. ATROPINA (U. S. P., B. P.), an alkaloid (C 17 H 2? NO 3 ) derived from bella- donna and forming white, acicular crystals, very little soluble in water, but soluble in alcohol and ether, and having a bitter taste. 0.0005-0.001 G., J-l mg. (- 2 o-rio S r - B - P -)- ATROPIN^E SULPHAS (U. S. P., B. P.), a white, crystalline powder, with a very bitter taste, soluble in water and alcohol. Dose, as for atropine. Oleatum Atropince (U. S. P.), 2 per cent. Unguentum Atropince (B. P.), 4 per cent. Liquor Atropince (B. P.), 1 per cent., -1 min. Lamellce Atropince (B. P.), gelatin discs, each containing ^^ gr. of atropine sulphate. HYOSCYAMINE is not procurable in even approximately pure form and might well be dispensed with, as it offers no advantages over atropine. HyoscyaminoB Sulphas (U. S. P., B. P.), ((C 17 H 23 NO 3 ) 2 H 2 SO 4 ), the sulphate of an alkaloid derived from Hyoscyamus niger. A crystalline, deliquescent powder with a bitter acrid taste, very soluble in water and alcohol 0005- 0.001G., i-lmg. (^o-eV.gr.)- Hyoscyamince Hydrobromidum (U. S. P. ), the hydrobromide of hyoscyamine, resembles the sulphate in most points but is not deliquescent. Dose, as of the sulphate. HyosdncB Hydrobromidum (U. S. P., B. P.), (C i; H 21 NO 4 HBr,3H 2 O), the hydro- bromide of hyoscine or scopolamine. It is obtained from hyoscyamus, scopola and other solanacese, and forms colorless, transparent crystals with an acrid, bitter taste, and is very soluble in water, less so in alcohol. 0.0003-0.0005 G. bcopolamince Hydrobromidum (U. S. P.) is identical with Hyoscine hydrobro- mide. HOMATROPIN.E HYDROBROMIDUM (U. S. P., B. P.), (C 16 H 21 NO 3 HBr), the hydrobromide of an alkaloid prepared from tropine by condensation with man- delic (oxytoluic) acid, a white crystalline powder soluble in 6 parts of cold water. Lamellce Homatropince (B. P.), homatropine discs, each weighing -$ gr. and containing T ^ gr. of homatropine hydrobromide. Therapeutic Uses. The numerous changes produced by atropine and its congeners on the organism would indicate for them a very wide sphere of usefulness were it possible to elicit their action on one organ without affecting others and this difficulty may perhaps be overcome in the future, when the different individuals of the series have been more carefully compared, and new tropeines and other modifications of the tropine radicle are available in therapeutics. ATROPINE SERIES. 293 The peripheral action of the whole series, as far as it is at present known, is so uniform that any member might be used to elicit it, but the only one that has come into general use for its peripheral effects is atropine. The purposes for which atropine is employed may be divided into groups as follows : To Arrest or Lessen Secretions. In rare cases of excessive salivation atropine has proved of service, but it is much more frequently used to lessen the joersgiration, especially in the later stages of phthisis. For this purpose comparatively small quantities, such as J mg. (%^-Q gr.) given by the mouth or hypodermically are generally sufficient, or the extract or tincture of belladonna may be used instead. In local sweating, it is often applied locally in the form of an ointment, lini- ment, or plaster, although Tappeiner has found that it has no effect when thus employed. Atropine is also used to arrest the secretion of the milk, for although it has not the immediate effects on the mammary that it possesses on the salivary glands, the secretion is diminished and eventually ceases under its influence, which prevents the gland receiv- ing any stimulation from the central nervous system. Belladonna is usually applied locally for this purpose in the form of the plaster, or less commonly as the ointment or liniment. To Paralyze the Cardiac Inhibitory Terminations. For this purpose a slightly larger quantity is required than is necessary to stop the secre- tions, and the administration of sufficient atropine to paralyze the vagus (1 mg.) therefore involves unpleasant dryness of the throat and diffi- culty in swallowing. In cases where slowing of the heart tends to be dangerous in itself, more especially in poisoning with certain substances to be discussed later, atropine is indicated. It may also be used for diagnostic purposes, to find if bradycardia is due to disease of the heart muscle or to inhibition. It may be repeated here that the resultant quickening is much less in old than in middle-aged people, and it is said that in many cases of old valvular lesion the administration of atropine is followed by little or no acceleration. Some forms of inter- mission of the pulse are due to unusual activity of the inhibitory appa- ratus, and these may be remedied by atropine ; but this intermission possesses little importance, and seems to require no therapeutic treat- ment. Atropine may be used to diagnose it from the more significant forms present in organic disease of the heart. The use of atropine to > paralyze the vagus terminations before the administration of an anes- thetic has been discussed already. (See page 176.) \* To Paralyze the Terminations of the Motor Nerves in the Iris and f Ciliary Muscles. It is used for this purpose largely in ophthalmology as a means of diagnosis and of treatment, and the precise conditions in which it is indicated may be treated better in text-books on this sub- ject than here. For these objects, solutions of the alkaloid al salts are generally applied to the conjunctiva, when enough of the alkaloid passes into the eye by a process of imbibition to produce marked local effects without affecting more distant organs. In order to dilate the pupil, extremely dilute solutions are used ; a few drops of a solution of one in 294 ORGANIC DRUGS ACTING AFTER ABSORPTION. 1,000, or even of one in 10,000, are quite sufficient. Much stronger solutions are required to paralyze the accommodation, and as a general rule 1 per cent, is used. These strong solutions produce complete paralysis in 1-1 \ hours, and the accommodation does not recover completely until after 5-7 days, while the pupil may not regain its normal size for 10-14 days. The application of even weaker atropine solution renders the sight imperfect for an inconveniently long period, and hyoscine and homatropine are therefore much used in its stead. The symptoms produced by a 1 per cent, solution of homatropine pass off, or at any rate become very much less marked in the course of 36 hours. These are consequently preferable for diagnostic purposes, while atropine is rather to be used where it is desirable to produce a paralysis of longer duration, as in various inflammatory conditions of the iris or cornea. Atropine is also preferable where complete paralysis of the accommodation is necessary, as homatropine often fails to effect this. Atropine and its congeners are contraindicated where there is any suspicion of glaucoma, as, owing to their action on the intraocular pressure, they may either aggravate the disease already present or pre- cipitate an acute attack. When dilatation of the pupil is necessary and there is reason to apprehend the results on the intraocular pressure, homatropine should be employed as its effects can be readily controlled by eserine. Numerous cases of poisoning have arisen from the exten- sive use of atropine in diseased conditions of the eye. It is often asserted that it passes down with the tears through the lachrymal duct and is absorbed from the nose, throat and stomach, but as a matter of fact it may be absorbed from the conjunctiva itself. The symptoms are generally only the milder ones of atropine poisoning dryness of the throat and slight excitement but dangerous and even fatal poison- ing has also arisen from its local application. In many cases this is due to the application of unnecessarily strong solutions to the eye, but, on the other hand, some patients seem abnormally sensitive to the action of atropine, and hyoscine, or better homatropine, ought to be preferred. In rare cases a curious inflammatory condition of the con- junctiva is set up by atropine, and this is often supposed to be due to the use of irritant preparations, but sometimes seems to follow the application of the absolutely pure alkaloid, and is apparently an idio- syncrasy ; it may, perhaps, be explained by the arrest of the ordinary secretions of the lachrymal gland and conjunctiva in these cases. Sometimes discs of gelatin impregnated with atropine or homatropine sulphate (B. P.) are applied to the conjunctiva instead of solutions of the salts. To Relax Spasm of the Intestines. In various forms of colic atro- pine is oFvery great service in lessening pain and allowing the passage of the intestinal contents ; for instance, it is preferable to morphine in lead colic, as it does not cause constipation. Hernia and volvulus are sometimes reduced by atropine injected hypodermically (3 mg. or JQ- gr.). It is often prescribed along with purgatives in order to lessen the griping which they produce, and has been used as a laxative in ATROPINE SERIES. 295 some forms of constipation with considerable success. For action on the bowel it is generally prescribed in pill form as one of the extracts of belladonna or hyoscyamus. The object of prescribing an impure preparation instead of the alkaloid is to allow of a strong local action y along the intestinal wall along with a slow and imperfect absorption, t - as the pure alkaloidal salts are liable to be absorbed in the stomach. To^Relax Spasms of the Involuntary Muscles of Other Organs. In Vthe spasmodic contraction of the ureters and bile jlucts due to calculi, atropine is occasionally prescribed either in the form of a pill or in solution for internal use, or by hypodermic application. In some forms of asthma due to contraction of the bronchial muscles, atropine has been applied locally by means of a spray or given internally, and stramonium leaves are often found of benefit when made up into cigar- ettes and inhaled when the attack comes on ; the smoke has been shown to contain small quantities of the alkaloids. Some cases of asthma are said to have been permanently cured by treatment with atro- pine internally. An ointment of atropine has also been applied to the cervix uteri with the hope of relaxing spasm during labor, but the results are somewhat questionable. Perhaps this action in relaxing spasmodic contractions of nervous origin may also explain the beneficial . effects obtained in cases of incontinence of urine in children in which j belladonna has long been the most reliable remedy. ToJLessen Pain. Belladonna liniment, plaster and ointment have /^long enjoyed a considerable reputation as local anodynes, and atropine has not infrequently been injected into painful areas. This anodyne action is very weak compared with that of cocaine, however, and the /? preparations of atropine have been less used of late years. In some i \ forms of gastralgia atropine has also been suggested. \V The Effects on the Central Nervous System of the members of this r group are very different, and the purposes for which they are used are diametrically opposite. Atropine is used as a stimulant in various conditions of depression of the brain and medulla oblongata. Thus, in collapse its hypodermic injection may be of use to stimulate the respiratory and vaso-constrictor centres, and at the same time to free tfie heart from excessive inhibition. In dangerous poisoning from narcotic and hypnotic drugs, more especially in opium poisoning, atropine has been largely used. A long and weary dispute as to the value of atropine in those cases has been carried on, for the history of which the reader is referred to the recent paper by Bashford. The results indicate that atropine is useful in morphine poisoning through stimulating the respiratory centre, which is the danger point. But it must be employed in small quantities (1.5 mg. or -fa gr.), as large doses, such as have frequently been advised, tend to depress the central nervous system and thus to aid rather than to antagonize the action of morphine on the respiration. It may be questioned whether in any case atropine may not be replaced by caffeine with advantage. The former stimulates the medullary centres but subsequently paralyzes them, while caffeine, even in comparatively large quantities, does not seem to have a depressant action in man. 296 ORGANIC DRUGS ACTING AFTER ABSORPTION. Atropine at one time had some reputation in the treatment of epi- lepsy. It has been shown both clinically and experimentally that this reputation was undeserved, the number of attacks and their violence being rather increased than diminished by its exhibition ; the belief in its powers arose from the use of impure preparations containing hyoscine. In some spasmodic diseases, such as whooping-cough, belladonna preparations have long enjoyed a wide reputation ; a possible explana- tion is that the hyoscine may allay the spasms by reducing the excita- bility of the respiratory centre. Hyoscine or scopolamine has been used as a narcotic to depress the central nervous system ; it is of great efficacy in insanity, producing Isound and ret resTTmg sleep, but is of less value in controlling the excite- ment during the day, and may in fact increase it. Hyoscine is also used with benefit in various forms of tremor of central origin, and. is said to lessen sexual excitement. Its hypnotic action does not seem to be of 'Tn*ig"*same^ "nature as that of opium, for in sleeplessness pro- duced by pain it is of comparatively little value, and it has no power to relieve pain itself. It differs from chloral in not producing deep sleep, for patients under the influence of hyoscine can always be aroused and are much less confused than after choral. The special indications ifor hyoscine seem to be sleeplessness due to abnormal activity of the taotor areas and some forms of tremor. Comparatively recently morphine and hyoscine have been injected as a preliminary to surgical operations, but as a general rule the nar- cosis induced is insufficient. As a preliminary to the use of ether the procedure seems to be of value, as much less of the anaesthetic is re- quired ; 10 mgs. (J gr.) of morphine and 0.3 mg. (^^ gr.) of hyoscine are injected two hours before the operation. Poisoning. In cases of poisoning with belladonna and its allies the treatment is purely symptomatic. In the excitement stage sedatives may be used ; perhaps chloroform and ether are best, as their effects are more transient than the others. Morphine has been advised, but its action on the respiratory centre renders its use dangerous, as in severe atropine poisoning the stimulation soon passes into depression, and the effects of the poison and its so-called antidote therefore sup- plement each other. Chloroform and ether, on the other hand, may be used to control the spasms and then stopped when these pass off. In the depression stage caffeine may be used, and eventually artificial respiration. Pilocarpine is of course useless, as it does not antagonize atropine in the brain, which is the point of danger. BIBLIOGRAPHY. Bezold u. Bloebaum. Untersuch. a. d. physiol. Laborator. zu Wiirzburg, i., p. 1. Heidenhain. Pfl tiger's Archiv, v., p. 309, and ix., p. 335. .Luchsinger. Ibid., xv., p. 482 ; xviii., p. 587, and xxvi., p. 459. Albertoni. Arch. f. exp. Path. u. Pharm., xv., p. 258. Hammerbacher. Pfliiger's Arch., xxxiii., p. 228. Mironow. Arch, de Scienc. biologique, iii., p. 353. Binz. Centralbl. f. klin. Med., 1893, p. 25. Ott. Therap. Gaz., 1887, p. 511. Alms. Arch. f. Anat. u. Phys., 1888, p. 416. ATROPINE SERIES. 297 Bayliss and Starling. Journ. of Physiol., xxiv., p. 99. Dixon. Ibid., xxviii., p. 57. Magnus. Ergebnisse der Physiol., ii. (2), p. 653. Riegel. Ztschr. f. klin. Med., xxxvii., p. 381. Schiff. Arch. f. Verdauungskrankh., vi., p. 107. Gottlieb. Arch. f. exp. Path. u. Pharm., xxxvii., p. 218. Cushny. Journ. of Physiology, xxx., p. 176, xxxii., p. 501. Bashford. Arch, internal, de Pharmacodyn., viii., p. 311. Vollmer. Arch. f. exp. Path. u. Pharm., xxx., p. 385. Levison. Berl. klin. Woch., 1894, p. 891. Orlowski. Diss., Dorpat, 1891. Mutter. Diss., Dorpat, 1891. Mathews. Am. Journ. of Physiol., iv., p. 482. Kochmann. Arch, internal, de Pharmacodyn., xii., p. 109. (Hyoscine.) Schiller. Arch. f. exp. Path. u. Pharm., xxxviu., p. 71. Anrep. Pfliiger's Archiv, xxi., p. 78. Schultz. Arch. f. Anat. u. Phys., 1898, p. 53. Thompson. Ibid., 1894, p. 117. Walti. Arch. f. exp. Path. u. Pharm., xxxvi., p. 411. Strieker u. Spina. Wiener Sitzungsber., Math.-nat. Classe, Ixxx., Abt. iii., p. 117. Spiro. Arch. f. exp. Path. u. Pharm., xxxviii., p. 113. Wiechowski. Ibid., xlvi., p. 154. Hedbom. Skandin. Arch. f. Phys., viii., p. 171. Compare also the Literature of pilocarpine and muscarine, nicotine and physostig- nrine. Agaricin. 1 White Agaric (Agaricus albus, Boletus Laricis), a fungus growing on the European larch tree, was formerly a purgative and antihydrotic of some repute. Its use to lessen the perspiration (antihydrotic) has been revived of late years, or rather a preparation known as agaricin and containing the active principle has been introduced into thera- peutics. Agaric or Agaricinic acid, the active constituent, belongs to the malic acid series and has the formula C 14 H 27 (OH)(COOH) 2 . Action. Both the acid and its sodium salt irritate the mucous membranes and wounded surfaces, and cause inflammation and even suppuration when injected subcutaneously. Large quantities irritate the stomach and intestine and cause vomiting and purging, but these are more liable to arise from the impure agaricin owing to its containing resinous acids. Injected into the frog, agaric acid paralyzes the central nervous system, weakens the heart and stops the secretion of the skin glands. In mammals the intravenous injection of agaric acid is followed by depression, weakness, dyspnoea. and death. The medulla oblongata is first stimulated and then paralyzed, as is shown by the blood-pressure first rising and then falling to zero, while the heart is primarily slowed by inhibitory action and later regains its rhythm, to eventually fail after the arrest of the breathing. Animals can only be poisoned with difficulty by the subcutaneous injection of agaricin, and no general symptoms are elicited when it is administered by the mouth. The most interesting feature of the action of agaric salts is the arrest of the sweat secretion, which is caused by peripheral action, for stimu- lation of the nerves of the cat's foot fails to elicit perspiration after its ingestion. It thus acts on the same peripheral mechanism as atropine in all probability, that is, on the terminations of the secretory nerves, but differs from atropine in acting only in the sweat glands, for the 1 Agaricin does not resemble atropine in its general action, nor in its chemical prop- erties, but it may be inserted at this point until these are more fully elucidated. 298 ORGANIC DRUGS ACTING AFTER ABSORPTION. saliva, tears and other secretions are not hindered by it, and may, in fact, be increased by its causing nausea. It is also devoid of action on the nerve terminations in the heart and pupil. Atropine acts much more powerfully than agaric acid, at least twenty times as much of the latter being required to arrest the sweat secretion. Uses. Agaricin is used in the night sweats of phthisis and other similar conditions and is generally given in pill form in doses of 5-60 mgs. (^-l g r -) The commercial agaricin often contains a large per- centage of impurities and has to be given in larger quantities, but the treatment ought to be begun with small doses. Tolerance is said to be acquired after some time, and the dose has then to be increased. The best results are got when the pills are taken 5-6 hours before retiring, as the acid is only slowly absorbed. If agaricin causes intestinal irritation and diarrhoaa it may be given with opium, but as in phthisis all irritation of the bowel is to be avoided, the remedy ought perhaps to be stopped when any such disturbance arises. Other antihydrotics are atropine and camphoric acid. Agaricin is preferable to atropine, because the latter tends to cause dry ness of the throat and other symptoms when it is given for some time even in very small doses. BlBLIOGEAPHY. Hofmeister. Arch. f. exp. Path. u. Pharm., xxv., p. 189. XIII. COCAINE, Cocaine is a comparatively recent addition to therapeutics, although the coca plant has been in use in South America for centuries. It is indigenous there, but has been introduced into India, Ceylon and Java. The leaves of the coca grown in Peru and Bolivia contain cocaine along with small quantities of other alkaloids, but the India coca and still more the Java leaves contain a smaller proportion of cocaine and a larger amount of the less known alkaloids. Cocaine, like atropine, is readily decomposed into several constitu- ents. On heating it with water, methyl alcohol is thrown off', leaving Benzoyl-ecgonine, which may be further broken up into benzoic acid and Ecgonine, a pyridine derivative. Ecgonine. Cocaine. CH CH CH'COOH N(CHJCH'OH N(CH)C L ' . L 1_ 'I 2 CH 2 Cocaine is capable of being changed in several different parts of its struc- ture. Thus ethyl or propyl may be substituted for the methyl group, the benzoyl radicle may be replaced by various others, such as cinnamyl, and so on. Many artificial cocaines have been formed in this way, and several of these have since been found in the cultivated plant, as for example Cinna- myl-cocaine, in which cinnamyl occupies the position of benzoyl in the above formula Various other alkaloids, such as Cocamine, Isococamine, Homococa- COCAINE. 299 mine and Homoisococamine are also present ; all of these contain the ecgonine molecule in combination with various acids, and cocaine may be formed from all of them by isolating the ecgonine and combining it with benzoic acid and methyl. These alkaloids are present in the plant in very small quantities compared with cocaine and have not been used therapeutically. 1 Another alkaloid which has been found in the Java coca is Tropacocaine, which is a combination of benzoic acid and a base (C 8 Hi 5 NO) which was formerly sup- posed to be identical with the pseudotropine derived from hyoscine, but has been shown to be of different constitution. It will be observed that the formula of ecgonine resembles very closely that of tropine, each containing the same nucleus, but differing slightly in the radicles attached to it. The most important effects of cocaine are those on the central nerv- ous system and on the sensory nerves. Symptoms. The symptoms of cocaine poisoning in man vary a good deal in different individuals. In most cases small quantities produce some excitement, pleasurable or disagreeable. The patient is gener- ally restless and more garrulous than in ordinary life, often somewhat anxious and confused. But very often a small dose is followed by a calm, languorous state, somewhat resembling that induced by small quantities of morphine, but differing from it in there being less tend- ency to sleep. The pulse is accelerated, the respiration is quick and deep, the pupil generally dilated, and headache and dryness of the throat are often complained of. The reflexes may be found somewhat more easily excited than usual and tremors or slight convulsive move- ments often occur. Later, powerful tonic or clonic convulsions super- vene, the heart becomes extremely accelerated, the breathing becomes rapid and dyspnoeic and may be finally arrested during a convulsion. In other cases the convulsive seizures are almost entirely absent and fainting and collapse occur. The skin is cyanotic and cold, the heart slow and weak ; the respiration is very much depressed and death fol- lows from its gradual cessation. Vomiting is occasionally seen at an early stage, but is not by any means common. In the dog, cat and rabbit the symptoms are invariably those of stimulation of the central nervous system. Soon after the injection, the animal shows symptoms of great restlessness and excitement ; it seems unable to keep still, the dog at first showing all the signs of affection and excitement which he displays on ordinary occasions on being unchained or taken for a walk, but afterwards running continu- ally in a circle and paying but little heed to anything around him. Still later regular convulsions occur, and these are at first clonic but may afterwards become tonic, and then resemble those seen in strych- nine poisoning. Even before the convulsions appear the animal seems partially unconscious, and in the intervals between them he lies in an apathetic state, which soon deepens to coma and death from asphyxia. In the frog a certain amount of stimulation of the central nervous system is often displayed after small doses increased movement, exag- gerated reflex and occasionally convulsions but these soon pass into 1 Hygrine, which was formerly supposed to be present in coca leaves, has been shown not to exist in them. 300 ORGANIC DRUGS ACTING AFTER ABSORPTION. depression and eventually total paralysis of the central nervous system, while the peripheral nerves still maintain their functions. General Action. Many of these symptoms point to a stimulant action on the Central Nervous System, resembling closely that seen in atropine poisoning. Thus the garrulity which is so often produced by cocaine, indicates an increased activity of the cerebrum, and the in- creased movement in the lower animals distinctly points to an affection of this part of the brain, for the movements are perfectly coordinated, and, in fact, in the early stages resemble exactly those performed by the normal animal in a condition of excitement. Further evidence of the action of cocaine on the cerebrum is offered by its effects on mus- cular work. The natives of Peru and Bolivia have used it for cen- turies to increase their endurance of fatigue. The bearers of the Andes, for example, march for hours and days with very little rest or food when they are supplied with coca leaves to chew. The effects of cocaine on the muscular power and on fatigue have been investigated also by means of the ergograph and dynamometer, and all observers are at one in asserting that much more work can be done after cocaine than before it, and that it has a surprising potency in removing fatigue. As regards mental work, its effects are less known, but on the analogy of caffeine it may be supposed to increase the mental powers also when taken in small quantities. Some travellers in South America relate marvellous tales of its producing feelings of the highest bliss and power, but these have not been confirmed by experience in the action of cocaine in less romantic regions of the globe. Cocaine in small quantities, then, increases the higher functions of the cerebrum, while in somewhat larger doses the stimulant effect spreads to the lower areas and produces a very great increase in movement, accompanied, it would seem, by a depression of the consciousness. At the same time, the coordinating or balancing powers seem affected, so that the animal generally moves in a circle, the symptoms resembling the forced move- ments often seen in affections of the cerebellum. The motor areas of the cerebrum have been found to be more easily stimulated by the electric shock when cocaine is injected, though when it is painted on the surface of the brain it lowers the irritability, owing to its action as a general protoplasm poison. Still larger quantities induce convulsions, which are not of spinal origin, but point rather to action on some undetermined part of the hind brain. At an early stage the medulla oblongata is affected, as is shown by the quickened respiration, and the exaggerated reflexes indicate stimulation of the spinal cord, which may be so great after very large doses as to cause convulsions like those produced by strychnine. The action of cocaine on the cen- tral nervous system is primarily a descending stimulation, the cere- brum being first affected, then the hind brain and medulla oblongata, and last of all the spinal cord. Perhaps it might be better expressed by saying that after small quantities the chief symptoms arise from the cerebrum, but as the dose is increased those from the lower parts I of the central axis tend to become more prominent. After the stimu- J COCAINE. 301 lation there succeeds depression, which follows the stimulation down- wards, affecting first the cerebrum and then the lower divisions. The two stages are not definitely divided, however, one part of the cere- brum often showing distinct depression, while another is still in a con- dition of excessive activity. In some cases, especially in man, the stage of excitement may be very short or apparently absent, and the whole course of the symptoms then points to medullary depression. The Respiration after cocaine is much accelerated owing to central stimulation. At first the depth of the movement is not changed, but as the acceleration progresses, the air inspired with eaeh breath gradu- ally becomes less. During the convulsions the respiration is irregular or ceases, but it recovers again in the intervals, until after a very vio- lent paroxysm it fails to be reinstated. In other cases the breathing becomes slower and weaker after a time, and eventually stops from paralysis of the centre. Periodic respiration is frequently seen, of the form generally known as Cheyne-Stokes'. (See Morphine, p. 213.) The Circulation is altered by cocaine owing to its action on the heart and on the vessels. The heart is much accelerated in mammals, while in the amphibians this is less often observed. The quickening has been ascribed to paralysis of the inhibitory terminations, but this seems not to be the case, for stimulation of the vagus slows the heart ; even late in the poisoning. The heart is accelerated, then, either by ^ J direct action of the muscle or by stimulation of the accelerator mech- { anism. It is often slow before death, but apparently not invariably/ and this is probably due to direct action on the muscle. In the frog's heart the inhibitory apparatus is paralyzed, the ganglia being affected in the same way as by coniine and other drugs. The vessels are much contracted in the earlier stages of poisoning, and this, together with the increased rate of the heart, leads to a very considerable rise in the blood-pressure. The constriction of the vessels seems partly due to stimulation of the vaso-constrictor centre, for sec- tion of the splanchnic nerves leads to an immediate fall in the arterial tension. But cocaine also exercises a direct action on the vessel walls, N for its local application leads to constriction of the vessels and C w blanching of the mucous membranes. It has not been determined^} as yet how far this direct action on the vessel walls affects the blood- pressure when cocaine is absorbed or when it is injected intraven- ously. The blood-pressure subsequently falls, apparently from periph- eral action, if Anrep's assertion that stimulation of the splanchnic then produces no further rise of pressure be correct. The effects on the peripheral Nerves and Muscles are disputed, for Mosso states that small quantities increase the strength of the muscular contractions on electrical stimulation both in man and animals, while others have failed to obtain any such effect. After the injection of cocaine, Anrep observed marked pallor of the Intestine and powerful peristalsis, while very large doses caused dila- tation of the mesenteric vessels and lessened the movements of the bowel probably through paralyzing the local nervous mechanism. 302 ORGANIC DR UGS A CTING A FTER ABSORPTION. The Urine is sometimes said to be increased by cocaine, while in other instances its injection has been followed by total anuria lasting for several hours. This suggests that the action is not a direct one on the kidney, but is caused merely through the changes in the calibre of the vessels. The other Secretions seem rather decreased than augmented, but no very marked effects are produced on them. The Temperature generally rises in cases of poisoning, sometimes as much as 3-5 C., from increased heat formation caused by cerebral action. Langlois and Richet observed that the higher the temperature of the animal the more easily were convulsions produced by cocaine and the more severe their type. It used to be supposed that cocaine retarded the Tissue Change and that less food was required when it was supplied. This was based on the statement of the endurance of the natives of South America when they were allowed to chew coca leaves, and on the discovery that the leaves also allay hunger to some degree. But the increase in the working power is due to the effects on the central nervous system, while the craving for food is prob- ably lessened owing to the cocaine inducing numbness of the sensory nerves of the stomach through its local action. A curious effect of cocaine, noted by Ehrlich in mice, is a widespread destruction of the hepatic cells, which become vacuolated and often necrosed. The liver is much increased in size and looks pale from fatty infiltration, which is also present, but which is not so characteristic as the vacuoles. Some cocaine is Excreted by the kidney in the dog when it is ab- sorbed into the blood, but 95 per cent, of that ingested is destroyed in the tissues, and this is the fate of all of it in the rabbit, in which this oxidation proceeds very rapidly. It is unknown whether it is oxidized in man, who is much more susceptible to its action than these animals. Local Action. Cocaine applied locally in most parts of the body ^ produces a loss of sensation through its paralyzing the Terminations of - some of the Sensory Nerves, particularly those conveying impressions vjpf pain and touch. It is often stated that the end organs of the nerves concerned with the feeling of heat and cold are also disorganized, but the exact researches of Kiesow show that this is incorrect, and that heat and cold are recognized as readily as in the unaffected parts of the body. Cocaine applied to the tongue removes the taste of bitter sub- stances, while sweet and acid fluids lose their taste only partially, and salt is recognized as easily as usual. 1 A solution applied to the nasal . mucous membrane paralyzes the sense of smell entirely. The anaesthesia or insensibility to pain and touch may be induced in any of the mucous membranes that can be reached by cocaine in sufficient concentration, pharynx, larynx, resophagus, stomach, nose, eye, urethra, bladder, 1 A curious contrast is presented in this respect by gymnemic acid, which is obtained from the Gymnema silvestre, and which removes the sensation of sweetness, while "bitter" is less affected and "acid" and "salt" are recognized as readily as usual. Gymnemic acid does not affect any other sense organs, as far as is known, and is, in fact, devoid of interest, except as regards its effect on taste. COCAINE. 303 vagina and rectum. Applied to the unbroken skin its effects are less marked, as it penetrates but slowly through . the horny epidermis ; but when the epidermis is removed by abrasions or by skin disease, the cutaneous organs of sensation are acted on in the same way as those of the mucous membranes. The deeper sensory terminations can also be acted on by hypodermic injection, which causes a feeling of numbness and the relief of pain in the part. Hypodermic injection reaches not only the nerve terminations of the subcutaneous tissues, but also the finer nerve bundles, and these too are rendered insensible as far as the solution extends to them. The part may therefore be cut into or be subjected to other surgical treatment without pain, as long as the knife does not pass beyond the area to which the drug has penetrated, and numbers of grave surgical operations have been performed under the local anaesthesia produced by cocaine. Injected into the neighborhood of a nerve trunk, cocaine penetrates into the fibres and induces anaes- thesia of the organs supplied by the nerve, and injected into the spinal canal, causes anaesthesia over large areas of the body, sometimes over almost the whole body ; this is probably due to its acting on the pos- terior roots of the cord. It must be noted that the anaesthesia is only produced by the local application of the drug. The internal admin- istration only leads to a partial loss of sensation in the throat and stomach, and no anaesthesia is induced by its action after it reaches the blood vessels. The reason for this evidently is that in order to paralyze the sensory fibres and terminations a considerable amount of the drug is required, but much less is necessary to paralyze the central nervous system. Even in the frog, the sensory terminations are not fully paralyzed until all symptoms of reflex excitability have disap- peared and total paralysis has supervened. A good deal of discussion has arisen as to whether the action on the sen- sory terminations is a specific one, or whether they are paralyzed before the motor endings simply because the cocaine comes in contact with them first whether, in fact, if both endings were exposed equally to the action of the drug, as occurs when it is distributed by the blood vessels, the sensory ter- minations would be specifically attacked and the motor left unaffected. The action was at first supposed to be a specific one on the sensory terminations, and it was stated that cocaine acted on the sensory terminations in the same selective way as curara does on the motor endings. There seems, however, to be no ground for supposing that this is the case. At the same time cocaine possesses a distinct selective power for the sensory nerve trunks con- veying sensations of pain, for when it is injected into the spinal canal, there is often complete insensibility to pain while warmth, cold and touch sensa- tions are still perceived and the motor functions are unchanged. When cocaine is applied locally to a mucous membrane it produces, besides a loss of sensation, a feeling of constriction and a distinct pallor and contraction of the vessels, which points to a local action on the vessel walls. The anaesthesia produced by cocaine is comparatively short, but varies with the strength of the solution applied and with the vascularity of the part ; as soon as the cocaine is absorbed, the local action disap- pears and sensation returns. 304 ORGANIC DRUGS ACTING AFTER ABSORPTION. Cocaine is applied to the Eye more frequently than to any other part. It produces local anaesthesia here, along with contraction of the con- junctival vessels, and this is followed by dilatation of the pupil and often by partial loss of the power of accommodation. The dilatation of the pupil is much less than that produced by atropine, and differs from it in several respects. Thus, the light-reflex is preserved, the pupil contracting in bright light arid dilating further in the dark ; a number of drugs which have little or no effect after atropine, contract the cocainized pupil (pilocarpine, muscarine, physostigmine), while atropine dilates it still further, and cocaine produces some dilatation after the full atropine action has been elicited. It is evident, then, that the two drugs produce dilatation by acting on different mechan- isms, and although the way in which cocaine dilates the pupil has been FIG. 28. Diagram of the innervation of the iris. P, a fibre of the motor oculi passing from the brain to the ciliary ganglion N, in which it terminates around a nerve cell, which sends an axis cylinder to terminate, M, in the circular fibres of the iris. R, a spinal nerve fibre issuing from the lower cervical cord, running through the stellate and inferior cervical ganglia and terminating around a ganglion cell in the superior cervical ganglion, G. The axis cylinder from this nerve cell runs to the iris (pass- ing the ciliary ganglion) and terminates in fibrils C, on the radiating fibres. C, is the point which cocaine stimulates and the resultant contraction of the muscle fibres causes dilation of the pupil, but when strong impulses descend to M, as happens when the eye is exposed to bright light, the circular muscle overcomes the weaker radiating fibres, and the pupil is contracted. In the same way strong stimulation of 3/by muscarine overcomes the stimulation of C by cocaine, while, on the other hand, when M is paralyzed by atropine and the circular fibres are thus thrown out of action, the radiating muscles are unopposed, and cocaine causes a greater dilatation than in the normal eye. a matter of dispute, the great majority of investigators now hold that it stimulates the terminations of the dilator fibres. (Fig. 28.) The motor oculi is not involved in its effects, unless very large quantities are applied, when its terminations may be depressed in the same way COCAINE. 305 as by atropine (Schultz). A strong argument in favor of the view given above has been found in the observation that when the dilator nerves degenerate, owing to removal of the superior cervical ganglion, cocaine fails to cause dilatation of the pupil. Several other symptoms are produced by the local application of cocaine to the eye, at any rate in some instances. Thus, the iris ves- sels are sometimes much constricted, the eye is more widely open than usual, so that the white sclerotic is seen above and below the iris, the whole eyeball is pushed forward (exophthalmos), and the intraocular tension is said to be considerably reduced. All of these features are produced only after cocaine has been applied in considerable quan- tity and for some time, and may be due, at any rate in part, to its absorption. They may all be observed in the un poisoned animal when the cervical sympathetic trunk is stimulated, and therefore seem to in- dicate a special action of cocaine on the centres or terminations of this nerve. All of these symptoms, except the anaesthesia and the pallor of the conjunctiva and iris, are produced by the injection of cocaine as well as by its local application, but in this case are prevented by pre- vious section of the cervical sympathetic. Cocaine does not produce any dilatation of the pupil in birds. Cocaine brought into immediate contact with nerve terminations paralyzes them, but this is true for so many other forms of living matter that it may be regarded as a General Protoplasm Poison. Thus muscles, nerves, and nerve ends cease to contract or to conduct stimuli when they are exposed to even very dilute solutions of cocaine ; the ciliated epithelial cells, leucocytes, and spermatozoa become motionless ; the cortical nerve cells lose their excitability, and many of the inverte- brates are killed by even a short exposure to cocaine. The move- ments of protoplasm in plants are also retarded or entirely suppressed by this poison, and the process of putrefaction is delayed considerably. In some cases, notably in the higher invertebrates, the final depression is preceded by a stage of increased movement, and it is said that the irritability of nerve is also augmented at first. In other instances, however, cocaine induces only depression and paralysis. Other examples of this destructive action are also seen in the thera- peutic use of cocaine, for the cornea is often rendered somewhat cloudy from its application, and its subcutaneous injection is sometimes followed by necrosis. Victims of the cocaine habit often show nu- merous scars on the arms and legs from this local gangrene, although this is probably often due to unsterilized syringes rather than to the solution. Most of the other natural alkaloids resemble cocaine in many points of their action, as far as they have been investigated, but some of the artificial compounds present divergences from the general type. Thus a number of them do not produce anaesthesia, although most of the nearly allied forms cause the characteristic changes in the liver cells ; some of them depart en- tirely from the typical cocaine action. Cocamine is often said to be a cardiac poison, but its action on the heart seems to resemble in general that of cocaine. It has, however, a much more 20 306 ORGANIC DRUGS ACTING AFTER ABSORPTION. intense action on muscular tissue, which it, like caffeine, throws into rigor mortis. Its anaesthetic power is very small. Some authorities regard the mus- cular action of caffeine as an important factor in its preventing fatigue, and the presence of cocamine in the coca leaves might be used to explain the similar effects induced by these, but the quantity is probably too small to have any noticeable action. Benzoylecgonine is a comparatively weak body, which produces symptoms resembling caffeine increased reflex excitability, muscular stiffness, and rigor and ecgonine is still less active, but elicits in frogs similar effects. Tropacocaine resembles cocaine very closely in its general action, but is less poisonous. It produces local anaesthesia more rapidly but for a shorter time than cocaine, and causes less dilatation of the pupil. PREPARATIONS. Coca (IT. S. P.), the dried leaves of Ery throxylon coca, containing 1-1 per cent, of cocaine. Fluidextractum Cocce (U. S. P.), 2-4 c.c. Q-l fl. dr.). Extractum Cocce Liquidum (B. P.), -1 fl. dr. Vinum Cocce (U. S. P.), 16 c.c. (4 fl. drs.). COCAINA (U. S. P., B. P.), an alkaloid (C 17 H 21 NO 4 ) obtained from the leaves of Erythroxylon coca and its varieties, forming colorless crystals with a bitter taste followed by numbness ; insoluble in water, soluble in alcohol. COCAINE HYDROCHLORIDUM (U. S. P., B. P.) (C 1? H 21 NO 4 HC1), colorless crystals, very soluble in water and alcohol ; watery solutions cannot be boiled as the alkaloid tends to decompose, 0.01-0.03 G. (- gr.). Lamellae Cocaince (B. P.), each contains -fa gr. of the hydrochloride. Injectio Cocaince Hypodermica (B. P.), 10 per cent., 2-5 mins. Unguentum Cocaince (B. P. ), 4 per cent. Oleatum Cocaince (U. S. P. ), 5 per cent. Trochisci Kramerice et Cocaince (B. P. ), each contains -fa gr. of the hydro- chloride. The Therapeutic Uses of cocaine are almost all dependent on its an- aesthetic action. It has been suggested as a brain stimulant in various conditions of mental depression, but has not been widely used for this purpose, which is better served by the less dangerous caffeine. A wine containing coca extract is often used in domestic medicine as a " general tonic," and has repeatedly given rise to the cocaine habit. Its anaesthetic properties render it extremely important. In oph- thalmic surgery it is used very largely both during operations and to alleviate pain, and occasionally to constrict the vessels of the iris in in- flammatory conditions. For complete anaesthesia a 4 per cent, solution may be employed, while to allay pain one of 1-2 per cent, is all that is necessary. The anaesthesia is of short duration, generally setting in after 5-7 minutes and passing off 20-30 minutes after the application of the drug. Occasionally cocaine, especially in strong solution, pro- duces a certain amount of opacity of the cornea, and it is stated that wounds heal less readily, and irritant antiseptics are more dangerous with cocaine than without it. This may sometimes be due to the use of impure cocaine, but it may be noted that cocaine is a protoplasm poison, and may therefore lessen the resistance of the tissues with which it comes in contact. The usual explanation given that cocaine paralyzes sensation in the cornea, and thus prevents the reflex winking COCAINE. 307 which removes foreign bodies from the surface and keeps the eye moist, is obviously insufficient, as the anaesthesia is of but short duration. The dilatation of the pupil produced by cocaine is much less complete than that under atropine, and can only be taken advantage of in diag- nosis by using very dim light, as the pupil contracts in bright light almost to its normal size. On the other hand cocaine is much less injurious in glaucoma and the dilatation can be removed at once by the instillation of a few drops of physostigmine. In the nose, throat and larynx, cocaine is used in a solution of 4 per cent., sometimes 10-20 per cent., and anesthesia is obtained with greater difficulty than in the eye, but the local contraction of the ves- sels is often of great service. Cocaine is used largely in operative procedure here and also in the treatment of irritable conditions of the respiratory passages, such as hay fever. In the urethra, rectum and vagina, cocaine may also be used either as an anaesthetic or to relieve pain temporarily. It is sometimes of service in painful or itching skin diseases, but care must be taken not to apply it to large broken surfaces, otherwise symptoms of poisoning may follow. The local action on the stomach is often valuable in checking vomiting due to gastric irritation. For many years after its introduction as a local anaesthetic in 1884, its use was practically limited to minor operations in the nose and throat and to ophthalmic surgery, few general surgeons venturing on its application in other fields. Within the last few years, however, its use has undergone a wide extension, so that almost all the major surgical operations have been performed under it, and local anaesthesia by means of cocaine or eucaine has now become a rival of ether and chloroform. Occasionally partial local anaesthesia is combined with the administra- tion of small quantities of chloroform or ether, which are insufficient to produce complete unconsciousness, but cause a numbing of the sensation, which, together with the local action, permits of a painless operation. At first strong solutions were injected to prepare the way for the knife, each step forward in the operation being preceded by an injection of cocaine to induce anaesthesia of the layer of tissue to be incised. But this method, which has been used chiefly by Reclus, required dangerous quantities of the drug, and is now scarcely used except for minor operations in which a single injection is sufficient. A more satisfactory method of local anaesthesia for operative purposes has been introduced by Schleich under the name of infiltration anesthesia. A large quantity, sometimes as much as 200 c.c. of a solution containing 0.01 per cent. 1 of cocaine and 0.8 per cent, of sodium chloride is allowed to permeate the tissues through a fine hypodermic needle. Only very slight pressure is required and the whole of the surrounding structures become swollen and oedematous and can be cut into without pain. Much of the fluid escapes through the incisions and no symptoms of poisoning arise. Schleich attributed the anaesthesia partly to the pressure exerted by the solution and partly 1 Some operators use a 0. 1 per cent, solution and then less is injected. 308 ORGANIC DRUGS ACTING AFTER ABSORPTION to the imbibition, but later investigators have found it to be dependent on the cocaine alone. 1 Another method (regional anaesthesia) is the injection of cocaine into the immediate neighborhood of the nerve supplying the part to be operated on. Complete local anaesthesia is obtained, and shock is less liable to occur than when general anaesthe- sia is induced (Crile). This method has been used extensively in operations on the foot and hand, for which it is admirably suited ; it is difficult to adapt it to other parts of the body. The local action in both infiltration and regional anaesthesia may be augmented and the danger of general poisoning lessened by retarding the circulation in the part to be operated on. This may be done by applying an Esmarch bandage above it when a limb is involved, or by the applica- tion of cold by means of ethyl chloride ; but the best results are obtained by using a 1 per mille solution of adrenaline along with cocaine. This contracts the vessels and arrests the circulation locally, and the cocaine thus remains longer unabsorbed. Braun recommends 3 drops of 1 per mille adrenaline solution to 50 c.c. of cocaine solu- tion for infiltration. After it was found that the nerve impulses from the periphery to the central nervous system could be blocked by the injection of cocaine into the peripheral nerves, the next step was to obstruct them higher in their course by applying it to the spinal roots (subarachnoid anaesthesia). The first to attempt this was Corning of New York, but the development of the procedure is due to Bier and Turner. A long hollow needle is passed into the spinal canal between the laminae of the lumbar vertebrae and 1 c.c. of a 2 per cent, solution of cocaine hydrochlorate is injected, after the withdrawal of an equivalent amount of cerebrospinal fluid. The actual amount of cocaine injected is thus 0.02 G. (J gr.). Within a few minutes numbness begins, generally in the feet at first, but sometimes in the lower part of the trunk ; it spreads upwards rapidly until sensibility to pain is lost everywhere below the diaphragm and sometimes in the thorax ; in some cases even the head has been found anaesthetized. The sensations induced by warmth and cold are less quickly affected, touch is preserved to some extent and the limbs can be moved readily, though the movements are carried out more slowly than usual ; the consciousness is unimpaired. This condition lasts from half an hour to an hour and then sensation returns gradually. " In the beginning of the action some muscular twitching is often seen, and the muscles are never relaxed as they are nnder chloroform or ether. Vomiting occurs in a large proportion of cases either during or after the operation, and persistent headache is generally present. The cocaine is believed to act on the posterior nerve roots and not on the cord itself. The cerebrospinal fluid has been found to contain a large number of polynuclear leucocytes after the injection and resumes its normal limpid character only after several days. This method of anaesthesia has been used in a large number of 1 Heinze showed that the morphine contained in Schleich's original fluid was super- fluous. COCAINE. 309 operations, some of them of the gravest nature ; it has also been sub- stituted for general anesthesia in labor. Of these methods, Schleich's infiltration has been most widely adopted and is admirably suited for minor operations. It is the safest method available for most of these, for the amount of cocaine injected ought not to be sufficient to induce poisonous symptoms, and should never exceed 20 mg. (J gr.) and much of this escapes by the incision. It requires some experience to induce complete insensibility to pain by this method and the operation has to be interrupted at intervals to permit of further injections. Some headache and nausea are occasional sequelae. When general anaesthesia is contraindicated, infiltration may be adopted in major operations, while on the other hand it is often contraindicated in minor operations where there is any possibility of complications, or where the anxiety and nervousness of the patient are likely to interfere with the proceedings. Subarachnoid or intraspinal cocainization is still on trial, and while it has been enthusiastically praised by some of its sponsors, it has in general been regarded as a hazardous method. Several fatalities are said to have resulted from it, and headache and nausea very often persist for many hours after the operation. It seems probable that it will in the future attract less attention than it has recently, and will be regarded as a last resort to be used when special circumstances contraindicate the general anesthetics and operation is imperative. Cocaine Habit. Since the introduction of cocaine into general thera- peutic use, numerous cases of the formation of a habit similar to that of opium or morphine, have been recorded. Some of these have been due to the attempt to substitute cocaine for morphine in the treatment of chronic morphinism, the treatment often resulting in the develop- ment of an irresistible craving for both alkaloids. The symptoms of cocainism generally begin with digestive disorders, loss of appetite, salivation and emaciation, but the more important changes occur in the central nervous system, which apparently undergoes degeneration simi- lar to that seen in chronic morphine poisoning. Sleeplessness, tremors and occasionally convulsions, hallucinations, insanity and delirium have been noted after long abuse, along with indefinite disturbances of sen- sation and motion. The treatirient of these cases is the withdrawal of the drug, and this can generally be done without the production of any special symptoms, though it is sometimes followed by great depression. This treatment is much facilitated by sending the patient to a special resort, and, in fact, is almost hopeless without his isolation. Acute Cocaine Poisoning is treated purely symptomatically. Amyl- nitrite has been advised when the blood-pressure seems much elevated, while for the convulsive attacks small quantities of chloroform or ether may be necessary. Of course, the stomach ought to be evacuated first of all if the drug has been taken by the mouth. 310 ORGANIC DRUGS ACTING AFTER ABSORPTION. Substitutes for Cocaine. Some artificial alkaloids have recently been introduced as local an- aesthetics instead of cocaine. The best known of these is Eucaine (C 15 H 21 NO 2 y which is much less poisonous than cocaine and differs from it in many points in its general action. In animals poisoned with large doses the central nervous system is first stimulated and then paralyzed ; the pulse is slowed from direct action on the cardiac mus- cle, and the blood-pressure falls. The terminations of the motor nerves are paralyzed in frogs, but only after the central nervous system. As a local anaesthetic it is almost as efficient as cocaine, and differs from it in not constricting the vessels or dilating the pupil. The intraocular pressure is said to be lessened, but this is not yet satisfactorily deter- mined. A 1-2 per cent, solution of the hydrochlorate is used in the eye, 2-5 per cent, for other mucous surfaces and for subcutaneous in- jection. Eucaine may be employed in 1 per cent, solution instead of cocaine for infiltration anaesthesia, and is less poisonous and can be dis- infected by boiling. The Orthoforms are still more recently introduced local anaesthetics, which may be mentioned here, although they resemble cocaine only in their action on the sensory terminations. They are methylesters of amidooxybenzoic acid (C 6 H 3 OH(NH 2 ) (COOCH 3 )), differing only in the positions of the hydroxyl and amido groups ; ancesthesin, the ethylester of amidobenzoic acid, and many other similar esters have more or less local anaesthetic power. Several other aromatic derivatives have long been known to have some numbing or anaesthetic properties, but have scarcely been used in therapeutics for this purpose. Even carbolic acid has a distinct numbing effect, and some of the antipy- retics have been proposed for use in ophthalmology. Orthoform is a white crystalline powder which has no taste or smell and is only very slightly soluble in water. It is used as a dusting powder or in ointment (10 per cent.), and is applied to painful surfaces, such as abrasions, ulcers or burns, either on the skin or on the visible mucous membranes (for instance, in laryngeal ulceration). In ulcer or cancer of the stomach, it has also been taken internally (0.1 G. in powder or tablets), and gives relief from the suffering. It is somewhat anti- septic and seems to be practically devoid of poisonous properties, except that slight corrosion is sometimes induced around the point of application. It has little or no effect on the sensibility of the unbroken skin, and its insolubility precludes its use by subcutaneous injection. The anaesthesia begins almost as soon as that induced by ordinary cocaine solutions, but lasts very much longer, because orthoform is dissolved and removed from the surface very slowly ; thus a single application of the powder causes anaesthesia for many hours, or even for some days. On the other hand, orthoform fails to penetrate the mucous membranes as cocaine does, and therefore only anaesthetizes when it comes into actual contact with exposed nerve ends. 1 Alpha-eucaine (C, 9 H 27 NO 4 ) was formerly used, but induces irritation at first, and is now seldom met with. Eucaine was introduced as Beta-eucaine. PILOCARPINE AND MUSCARINE. 311 Another series of local anaesthetics has been introduced by Trplldenier under the name of Acoines. They are derivations of phenylguanidin and are said to be much less poisonous than cocaine and to induce complete an- aesthesia of the cornea and conjunctiva and also to be available for infiltration anaesthesia. Holocaine, a derivative of phenacetine, has been recommended in ophthalmological operations, but is more poisonous than eucaine, and presents no equivalent advantages. BIBLIOGRAPHY. v. Anrep. Pfluger's Archiv, xxi., p. 38, 1880. Mosso. Arch. f. exp. Path. u. Pharm., xxiii., p. 153. Pfliiger's Archiv, xlvii.,p.553. Alms. Arch. f. Anat. u. Phys., 1886. Supplement, p. 293. Kiesow. Wundt's Philosoph. Studien, ix., p. 510. Stockman. Brit. Med. Journal, 1889, i., p. 1043. Poulsson. Arch. f. exp. Path. u. Pharm., xxvii., p. 301. Ehrlich. Deutsch. med. Wochenschr., 1890, p. 717. Ehrlich u. Einhorn. Bericht. der deutsch. chem. Gesellsch., 1894, p. 1870. Fitehne. Berl. klin. Woch., 1887, p. 107. Limbourg. Arch. f. exp. Path. u. Pharm., xxx., p. 93. Eeichert. Philadelphia Med. Journ., 1902. Mannheim. Ztschr. f. klin. Med., xviii., p. 380. Marci.nowskL Deutsch. Ztschr. f. Chir., Ixv., p. 417. (Eucaine.) Francois- Franck. Arch, de Phys. (5), iv. , p. 562. Chadbourne. Brit. Med. Journ., 1892, ii., p. 402. (Tropacocaine.) Vinci. Virchow's Arch., cxlv., p. 78. (Eucaine.) Arch. f. Anat. u. Phys., 1897, p. 163. Virchow's Arch., cxlix., p. 217; cliv., p. 549. Einhorn u. Heinz. Munch, med. Woch., 1897, p. 931. (Orthoform.) Soulier et Guinard. Arch, internat. de Pharmacodyn., vi., p. 1. Wiechowski. Arch. f. exp. Path. u. Pharm., xlvi., p. 154. Heinze. Virchow's Arch., cliii., p. 466. Trolldenier. Therap. Monatsh., 1899, p. 36. (Acoines.) Sraun. Arch. f. klin. Chir., Ivii., p. 370 ; Ixix., p. 541. Bier. Ibid., Ixiv., p. 236. Valenti. Arch. Ital. de Biol., xxxix., p. 253. Orile. Journ. Amer. Med. Assoc., Feb. 22, 1902. Lea. Journ. of Obstet. and Gynecol., i., p. 71. Terrett. American Medicine, 1901, ii., p. 417. XIV. PILOCARPINE AND MUSCARINE. Pilocarpine and muscarine, two alkaloids of very different chemical constitution, possess similar properties from a pharmacological point of view. Pilocarpine (C U H 16 N 2 O 2 ) 1 is found along with Isopilocar- pine in the leaves of several species of Pilocarpus. Muscarine, the alkaloid of one of the poisonous mushrooms, 2 Agari- cus muscarius, or Amanita muscaria, is very closely related chemically to choline, which is a constituent of several animal tissues. It may probably be represented by the formula CH (OH) 2 JH. [ 2 -N(CH 3 ) 3 OH 1 The structural formula of pilocarpine is not yet definitely determined. Pilocarpi- dine has been isolated from the leaves of Pilocarpus Jaborandi only and is practically inert. Jaborine was formerly stated to occur with pilocarpine and to possess an action resembling that of atropine, but more recent investigators have failed to confirm either of these statements. 2 Muscarine is accompanied in the Amanita by another poison which differs from it- in inducing convulsions and other symptoms of central nervous stimulation; the symptoms of amanita poisoning are a mixture of those caused by these two poisons (Harm sen). 312 ORGANIC DRUGS ACTING AFTER ABSORPTION. A substance almost identical with muscarine from the chemical stand- point has been prepared by the oxidation of choline, but this synthetic muscarine differs in its action from the natural alkaloid in several respects. A number of other nearly related bodies (trimethylammo- nium bases) resemble muscarine in some points of their action, but are not so poisonous, and fail to act on several of the organs affected by the base derived from the mushroom. Muscarine, pilocarpine and isopilocarpine resemble each other in action ; muscarine is much more poisonous than pilocarpine, which is again eight times as active as isopilocarpine. Pilocarpine and muscarine stimulate the terminations of certain nerves supplying mistriated muscle (except that of the vessels), the heart and secretory epithelium. Their effects are therefore diametri- cally opposed to those of atropine in the peripheral organs. Symptoms. The symptoms of poisoning in man 'commence with a very marked secretion of saliva, followed soon after by excessive per- spiration and a flow of tears. After muscarine and sometimes after pilocarpine, nausea, retching and vomiting, pain in the abdomen and violent movement of the intestines causing profuse watery evacuations, are next observed. The pulse is sometimes quickened, sometimes very slow and irregular ; the pupil is contracted, and the sight is accommo- dated for near objects. The respiration is often quick and dyspnoeic, and rales may be heard over the bronchi, denoting an accumulation of mucus in them. Giddiness and confusion of ideas are complained of, and after pilocarpine tremors and feeble convulsive movements are sometimes observed, but the nervous symptoms are not so conspicuous as those from the peripheral organs. Eventually the respiration be- comes slower and great weakness in the movements manifests itself, but the consciousness remains more or less perfect till the breathing ceases. Action. The salivary and lachrymal Glands, the mucous glands of the mouth, throat, nose and deeper respiratory passages, the gastric secretory glands, the pancreas, and probably the intestinal glands, all secrete copiously after muscarine and pilocarpine. The sweat glands and the ceruminous glands of the ears are likewise roused to unwonted activity, and many other glandular structures are also stimulated. 1 In most cases the solids of the secretions are increased as well as the fluids, although to a somewhat less extent. The, bile, the urine and the milk do not seem to be affected directly by pilocarpine and muscarine, although they may be reduced in amount or otherwise modified by the withdrawal of large quantities of fluid from the body by other channels. After a small quantity of atropine, pilocarpine and muscarine in ordinary quantities produce no increase in any of the secretions. This indicates that the seat of action of these poisons is not the secretory cells, for it has been shown that atropine paralyzes only the termina- 1 A curious example of this has been shown by Dreser to occur in the fish, in which the swimming bladder secretes more oxygen than usual. PILOCARPINE AND MUSCARINE. 313 tions of the secretory nerves and leaves the cells uninjured. On the other hand, section of the secretory nerves does not alter materially the action of pilocarpine or muscarine, for the secretion of perspira- tion in the foot of the cat is increased by pilocarpine even after section of the sciatic nerve. The seat of action of pilocarpine and muscarine is therefore the terminations of the secretory nerves the minute fibrils which ramify between the epithelial cells ancTper liaps even enter them. These fibrils are stimulated by the members of this group and para- lyzed by atropine, and these two series therefore form antidotes to one another. The salivary secretion may amount to half a litre or more in the course of 2-3 hours after an injection of pilocarpine, while the skin and lungs excrete even a larger quantity of fluid in the same time. The weight is thus considerably reduced by pilocarpine owing to the loss of fluid, which may, according to some authors, amount to 2-4 kilogrammes (4J-9 Ibs.) after a single dose. The secretion of the milk is not increased by pilocarpine, but the percentage of sugar in it is stated to be larger than usual. Ube sugar of the blood has been found increased by pilocarpine, and this lias been attributed to its acting on the terminations of the nerves in the liver which regulate the glycogenic functions of that organ. The increased activity of the glands is accompanied by an accelera- tion of the blood current through them, but this is a result of their stimulation from any cause whatever, and is probably not due to the direct action of the alkaloids on the vessels. The redness of the skin, especially of the face, so often observed after pilocarpine, may perhaps be explained in this way, as an accompaniment of the augmented ac- tivity of the sweat glands. It was formerly supposed that pilocarpine acted on the same structures as nicotine the sympathetic ganglia but this is disproved by the sweat secre- tion of the foot after section of the sciatic, for no sympathetic ganglia have been found in connection with these sweat glands except those in the pelvis. Another question which has been the subject of prolonged and somewhat bitter discussion is whether pilocarpine and muscarine can act at all after atropine. It seems now to be admitted that while minute quantities of the latter stop secretion set up by ordinary doses of pilocarpine and mus- carine, yet either of these in very large quantities will reinstate it, and this alternation of stimulation and depression may be repeated a number of times. After a prolonged stage of stimulation large quantities of pilocarpine or muscarine eventually paralyze the nerve terminations, and the secretions are therefore diminished or stopped entirely. But this never occurs save in ex- periments on animals, for, as a general rule, the respiration is paralyzed by smaller quantities than are necessary to elicit this feature. Muscle. Nausea and discomfort in the stomach, followed by retch- ing and vomiting, are rarely seen after pilocarpine, but form some of the earliest symptoms of muscarine poisoning. They are not produced by the saliva swallowed, as was formerly supposed, but by a stimula- tion of the terminations of the pneumogastric in the muscular coats of 314 ORGANIC DRUGS ACTING AFTER ABSORPTION. the stomach, similar to that of the terminations of the secretory nerves. This is, perhaps, incapable in itself of producing complete evacuation of the stomach, but may set up a reflex contraction of the muscles of the abdominal wall which accomplishes it. C The intestines are also set in unusually active movement by a similar "/process, and' repeated evacuation of their contents follows. These are at first of firm consistency, but later, as the continued peristalsis carries down the contents of the small intestine, which have not lain long enough in the bowel to allow of the absorption of their fluid, the faeces contain more water than usual. This fluidity of the stools may also be due in part to an augmentation of the intestinal secretion, but this has not been satisfactorily demonstrated. Even after the bowel has been completely evacuated, the persistent peristalsis betrays itself in painful straining. /^ The muscle of a number of other organs contracts after pilocarpine \ or muscarine, also, it is believed, from stimulation of the nerve ter- xr minations. Thus the ^(^pi. bladder* bronchial muscles, and possibly I the uterus, are contracted, and in the case of the bladder repeated \evacuation and straining may occur. Of much greater importance than these is the effect of pilocarpine and muscarine on the eye. In poisoning with these and also on local application, the pupil becomes extremely narrowed, and at the same time the ciliary muscle contracts so that the lens is accommodated for short distances. Both of these phenomena are due to_imjiajtiQ_n pf the terminations of the mofor oculi in the intraocular muscles (see Fig. 26, p. 287) ; they are not equally easily elicited, however, for according to Krenchel, muscarine acts on the ciliary muscle much more readily than on the pupil, so that occasionally the sight may be accommodated for short distances while the pupil remains fairly wide. The intraocular pressure is reduced by muscarine and pilocarpine, although they may increase it at first. This has riot been explained, but is often said to be associated with the changes in the pupil, myosis (contraction of the pupil) being generally attended by a reduced tension. The stimulant action of pilocarpine on the terminations of the motor oculi terminates in depression and con- sequent slight widening of the pupil. All these muscular phenomena are prevented by the previous ad- ministration of atropine. This antagonistic action has been carefully studied in the eye, where it is found that after pilocarpine has pro- duced contraction of the pupil, the administration of very small quan- tities of atropine is followed by dilatation. Strong pilocarpine solution again dropped into the eye will again reduce the size of the pupil, but the quantity required is vastly more than in the normal eye, and this second contraction may again be removed by comparatively small quantities of atropine. In the bird's pupil, in which the muscle is striated, muscarine and pilocarpine have no effect, the terminations of the nerves being evidently different from those in mammals. The action of pilocarpine and muscarine on the Circulation presents some differences in different species of animals. On the applica- PILOCARPINE AND MUSCARINE. 315 tion of either to the frog's heart, its rhythm is at once slowed, the diastolic pause being much increased in length and the contractions lessened in force. Soon the heart ceases to beat entirely, although irritation of its muscle by mechanical or chemical means elicits one or more contractions. A number of drugs which stimulate the heart muscle, such as physostigmine or digitalin, induce weak rhythmical contractions, but atropine in the minutest quantities restores the heart to its normal rhythm and strength. The symptoms produced are ex- actly those seen on stimulation of the vagus by electrical shocks, and muscarine has long been believed to act by stimulation of the inhibi- tory mechanism in the heart. It is generally stated that the site of its action is the ganglia on the course of the vagus, but this is incor- rect, for muscarine acts on the apex of the frog's ventricle, in which no ganglia whatever have been found. Muscarine, therefore, stimu- lates the terminations of the vagus fibres in the heart muscle, and thus produces slowing and eventually standstill. Atropine removes this standstill by paralyzing the terminations, but larger quantities of muscarine or pilocarpine will again overcome the atropine action and restore the standstill or, at any rate, the slow pulse. Digitalin and its allies remove the standstill by increasing the irritability of the muscle until the inhibition can no longer hold the heart in check, but throughout the rhythm caused by these the activity of the vagus can be seen in the slowness of the beat and the prolongation of the diastole. The vagus ends are eventually paralyzed by pilocarpine and the heart resumes its normal rate. Larger quantities, however, again slow it owing to direct action on the cardiac muscle. In rabbits and cats similar changes are seen in the circulation after muscarine. The heart is slowed or brought to a complete standstill, the blood pressure falls, and all the symptoms produced by anaemia of the brain may follow, but the animal becomes again perfectly nor- mal on the administration of small quantities of atropiue. The fall in blood-pressure is often greater than is accounted for by the slowing of the heart, and the peripheral vessels are extremely congested. This may possibly be due to the dilatation of the vessels which, as already stated, accompanies the increased activity of the glands. Pilocarpine differs from muscarine here in several particulars, for it soon depresses the inhibitory fibres and the heart regains its former rhythm, but the cardiac muscle is then affected, so that the contractions rapidly be- come weaker and slower again, and this secondary slowing is not re- moved by atropine ; the vaso-motor centre also becomes gradually weakened by large doses, so that the blood vessels remain somewhat dilated, and the arterial tension remains low even after atropine. In dogs, the stimulation of the inhibitory fibres seems sometimes to be entirely absent after pilocarpine and muscarine, and in man this is very frequently the case. Instead of a slow pulse and lessened ten- sion in the arteries, acceleration and increased blood-pressure are then observed. This is accompanied in man by marked palpitation and discomfort in the region of the heart and by dilatation of the skin 316 ORGANIC DRUGS ACTING AFTER ABSORPTION. vessels, especially of those of the face. In other cases, however, the same circulatory disturbances are produced as in the cat and rabbit. (Fig. 29.) No explanation of the acceleration of the heart has been FIG. 29. B A Tracings of the movement of the auricle (upper) and ventricle (lower) of the dog under muscarine. During contraction the levers move upwards ; during relaxation downwards. A-B, normal. At B, muscarine was injected intravenously and at C it began to act. The movements of the ventricles are slower and a distinct pause is seen in diastole. The contraction is less complete, while the heart relaxes more than usual during diastole. The auricle soon comes to a standstill in diastole. Com- pare the effects of stimulation of the vagus in the first part of Fig 27, page 289. offered, but Howell has found acceleration constantly produced by mus- carine in the crab's heart. In embryo hearts, muscarine, in ordinary quantities, produces no change whatever during the first 150 hours of life (in the chick). The explanation of this phenomenon is that the inhibitory nerves have not been developed at this stage, and after their development is complete, muscarine acts on the heart as in the adult. The absence of slowing in some of the invertebrates may be due to a similar cause, although this does not held good for the crab, in which there is a well-defined inhibitory apparatus. The Respiratory centre is not acted on directly by small quantities of pilocarpine and muscarine. But the changes in the circulation lessen the amount of blood passing through the lungs, and the contrac- tion of the bronchial muscle may seriously retard the movement of the air and thus impair the aeration of the blood. This bronchial constriction may be the explanation of the O3dema of the lungs which is often observed in cats and rabbits poisoned with the members of this series, and which has also occurred in fatal poisoning in man. Large quantities of pilocarpine cause a tendency to convulsive movements and a more rapid and labored respiration. Eventually the respiration becomes slow and weak and asphyxia follows. It has been found that pilocarpine increases the Leucocytes of the blood, and this is generally attributed to Iti=T acting on tne tissues which form leucocytes, an explanation which is supported by the PILOCARPINE AND MUSCARINE. 317 statement of Ruzicka, that the Malpighiau corpuscles of the spleen are increased in number after pilocarpine. The Temperature is said to be increased by pilocarpine, although only to a very small extent, and the carbonic acid excretion is increased through the drug increasing the activity of the glands and other organs. After the perspiration is fully developed the internal tem- perature is generally reduced, especially in fever. Some symptoms occur in cases of poisoning which point to some action of the alkaloids on the Central Nervous System. Thus frogs develop well-marked convulsions, and even in the higher animals and man tremor and slight convulsive movements, such as hiccough, have been observed. In the later stages muscular weakness is developed, and the slow respiration and the fall in blood-pressure also indicate a central action, which seems to be confined to the lower parts of the nervous system, however, for consciousness remains little altered. These symptoms may be complicated by marked convulsions which appear to be due to the anaemia of the brain and do not denote any direct action on that organ. Pilocarpine and muscarine, while resembling each other in general, present some points of difference, which are of the greatest importance as regards their use in therapeutics. Muscarine has practically never been introduced into medical practice, because, while its action on the secretions is quite equal to that of pilocarpine, the gastric symptoms are produced much more readily by it. It is also a very much more powerful poison than pilocarpine, and is much less easily prepared in pure form. PREPARATIONS. (Muscarine is not used in therapeutics.) Pilocarpus (U. S. P.), Jaborandi Folia (B. P.), the dried leaflets of Pilo- carpus Jaborandi l (and of P. Selloanus, U. S. P.). Fluidextractum Pilocarpi (U. S. P.), -2 c.c. (8-30 mins.). Extractum Jaborandi Liquidum (B. P.), 5-15 mins. Tinctura Jaborandi (B. P.), -1 fl. dr. PILOCARPINE HYDROCHLORIDUM (U. S. P.) (C U H 16 N 2 O 2 HC1), the hydro- chlorate of an alkaloid obtained from Pilocarpus, forms small, white crystals, odorless, with a slight bitter taste, deliquescent in the air, very soluble in water and alcohol. 0.003-0.03 G. (^-% gr.). PILOCARPINE NITRAS (U. S. P., B. P.) (C 12 H 16 N 2 O 2 HNO 3 ), the nitrate of an alkaloid obtained from Jaborandi leaves, forms a white crystalline powder, which is soluble in 8-9 parts of cold water, and is freely soluble in hot alcohol. *Vi gr- The preparations of the crude drug are but little used, as they vary greatly in their activity and cause nausea and vomiting more readily than the alka- loidal salts. This is explained by the fact that they are absorbed more slowly from the alimentary canal, and therefore have longer time to produce their characteristic effects upon it. Therapeutic Uses of Pilocarpine. Its action on the sweat glands renders pilocarpine much the most powerful diaphoretic in the gharma- 1 Pilocarpus Jaborandi leaves are now extremely scarce and have been supplanted by those of Pilocarpus pinnatifolius and P. microphyllus. 318 ORGANIC DRUGS ACTING AFTER ABSORPTION. copoeia, and it is used internally almost exclusively for this purpose. In various conditions in which excess of fluid accumulates in the body, pilocarpine may be exhibited to remove it. In dropsy, especially that due to renal disease, a few injections frequently reduce the fluid and remove the effects of the accumulation, although they do not, of course, aftect the diseased tissues directly. By unburthening the blood and tissues of their excessive fluid, however, pilocarpine may improve the nutrition of the kidney, and thereby promote its recovery. In dropsy due to heart disease pilocarpine must be used with caution, owing to its exercising a depressant action on the circulation, perhaps on the heart itself. In some other pathological exudations pilocarpine has also been advised, as in pleural, pericardia! and subretinal effusion. It must be remembered that after the diaphoresis produced by pilocarpine there usually sets in a period of depression, weakness and languor, and this may be sufficient to counteract the improvement obtained by the re- moval of the fluid. It is still a disputed point whether pilocarpine possesses any advantage as a diaphoretic over the other means of pro- ducing sweating, such as hot or cold packs. Its advocates point to the fact that much less disturbance of the patient is required, and that the subsequent depression is not greater, while its opponents assert that the hot or cold pack produces less depression and is not accompa- nied by the unpleasant salivation and occasional nausea of pilocarpine. Accumulations of fluid in the body may also be removed by way of the bowel by the use of a hydragogue cathartic or preferably a saline purgative, or the kidney may be stimulated to special activity by the use of such diuretics as theobromine and caffeine. The last method of treatment is that generally preferred as it induces less weakness and depression subsequently than either of the others. In uraemia pilocarpine sometimes proves of great benefit if exhibited earTy, and it has been supposed that this was due to the skin taking up the renal function vicariously and eliminating the poison. Some support has been given this explanation by the discovery of traces of urea in the perspiration after pilocarpine, but it is now recognized that the urea is not the poisonous principle in uraemia, and the beneficial effects are probably due rather to the removal of fluid and the relief of the overstrained circulation. It has also been suggested that pilo- carpine acts directly on the kidney, and an increase in the urine is not infrequently seen after several injections ; but this is to be ascribed rather to the changes in the circulation following the removal of the fluid than to any direct action on the renal epithelium, for which there does not exist any satisfactory experimental evidence. Pilocarpine has been used in a number of fevers and in diphtheria and syphilis, but no sufficient evidence of improvement in those con- ditions has been brought forward. In ophthalmic surgery pilocarpiue has been employed as a substi- tute for physostigmine, to contract the pupil and reduce the intraocular pressure. For this purpose a very dilute solution of the salts (2 per cent.) may be used, or lamellae of gelatin may be prescribed, each con- PILOCARPINE AND MUSCARINE. 319 taining i mg. (^i gr.), to be laid on the conjunctiva. The contraction of the pupil generally attains its maximum in about J-l hour, and passes off in 3-5 hours ; it is generally less complete and of shorter duration than that seen after physostigmine. Pilocarpine first in- creases and then lowers the intraocular tension. I n various diseases of the ear, pilocarpiue has been used with good effects m"some cases, ftut it is quite unknown how it acts here. The conditions in which it is of service are various forms of labyrinthine disease, and some forms of effusion into the tympanic cavity. Pilocarpine was at one time recommended us an ecbolic 1 and several cases of abortion have been ascribed to its use. Further experience has led to the conclusion, however, that if it possesses any action whatsoever on the pregnant uterus it only does so when administered in quantities which produce undesirable secondary symptoms. Pilocarpine is frequently prescribed in lotions for the hair, and a renewed growth of the hair has been frequen tly seen _in alopecia treated iiithis way. This has been explained by its action on the glands of tlu> skin, increasing the moisture of the scalp and improving its circu- lation and nutrition, but Tappeiner found that the local application I of pilocarpine to the skin produced no increase in the secretion of the,/ glands. In cases of atropine poisoning, large doses of pilocarpine have been ordered with alleged good results. In animal experiments, however, the quantity of pilocarpine necessary to antagonize even small doses of atropine has been found to be so large that there is little reason to hope for improvement from its administration in poisoning in man, especially as the action of atropine on the central nervous system is not antagonized by pilocarpine. In poisoning from pilocarpine or muscarine small quantities of atropine are the antidote recommended alike by pharmacological experiment and by clinical experience. Muscarine Intoxication. In Siberia the Agaricus muscarius is used to form an intoxicating beverage. The symptoms produced are hilarity and jollity, and the victims declare themselves to be more capable of fatiguing exertions than they would be without the preparation. Eventually giddiness and somnolence are produced, and after large quantities vomiting and convulsive" attacks may follow and eventually prove fatal. The exhilarating effects are probably due to the presence of a poison discovered by Harmsen and not to the muscarine. This new poison seems to play a role at least as important as that of mus- carine in cases of amanita poisoning ; it is not antagonized by atro- pine, and its chemical nature is unknown. 1 An ecbolic is a drug used to evacuate the contents of the uterus. 320 ORGANIC DRUGS ACTING AFTER ABSORPTION. BIBLIOGRAPHY. 1 Muscarine. Schmiedeberg u. Koppe. Das Muscarin. Leipzig, 1869. Krenchel. Arch. f. Ophthalm., Bd. xx., p. 135. Ringer. Journ. of Phys., iii., p. 115. Gaskell. Phil. Trans. Roy. Soc., 1882. Journ. of Physiol., iii., iv., viii. Dixon and Brodie. Journ. of Phys., xxix., p. 155. Harmsen. Arch. f. exp. Path. u. Pharm., 1., p. 361. NolhnageL Berichte der Berl. Chern. Gesellsch., 1893, i., p. 801. Schultz. Arch. f. Anat. u. Phys., 1898, p. 73. Pilocarpine. Langley. Journ. of Anatomy and Physiol., x., p. 187. Journ. of Physiol., i., iii. Cf. Nicotine. Luchsinger. Pfliiger's Archiv, xv., p. 482 ; xviii., p. 501. Lewin. Charite-annalen, v., p. 489. Ringer and Murrell. Journ. of Physiol., ii., p. 135 ; Practitioner, xxvi., p. 5. Albertoni. Arch. f. exp. Path. u. Pharm., xi., p. 415. Nawroeki. Centralbl. f. d. med. Wissensch., 1878, p. 97. Harnack u. Meyer. Arch. f. exp. Path. u. Pharm., xii., p. 366. Frank and Voit. Ztschr. f. Biol., xliv., p. 111. Schlegel. Arch. f. exp. Path. u. Pharm., xx., p. 271. Schi/. Archiv f. Verdauungskrh., vi., p. 107. Marshall. Journ. of Physiol., xxxi., p. 120. XV. PHYSOSTIGMINE. Physostigmine or Eserine is the chief alkaloid of the Calabar bean, or Ordeal bean (Physostigma venenosum), which grows in Western Africa and was employed there by the natives in the trials by ordeal for witchcraft. Either physostigmine itself, or a nearly allied alkaloid, occurs also in the Kali or Cali nuts, the seeds of Mucuna urens. The constitution of physostigmine (C 15 H 21 N 3 O 2 ) is still unknown. Two other alkaloids have been found in the extract of the Calabar bean and are probably products of the decomposition of physostigmine, which is a very unstable body. These are Calabarine, which resembles strych- nine in its effects, and Eseridine, which acts in the same way as physo- stigmine, but is much less poisonous. Physostigmine produces a number of symptoms resembling those of muscarine and pilocarpine poisoning, and many authors describe all three together, but it departs in certain points from the type of these two drugs, and according to one theory acts upon a different set of tissues. Symptoms. The symptoms of poisoning vary but little in different animals ; in the dog and rabbit the first results of a large dose of physostigmine are weakness in the voluntary movements and a curious tremor and muscular twitching, beginning in the hind legs, but soon extending over the whole body. The animal falls on one side and can not raise itself again, although it makes efforts to do so when touched. a The literature of muscarine and pilocarpine is so mixed with that of atropine, nico- tine and physostigmine, that a complete list would involve numerous repetitions. I must, therefore, refer those interested to the bibliography given under those groups, and shall mention here only the papers which deal very largely with muscarine and pilocarpine. PHYSOSTIGMINE. 321 The saliva and tears are increased, the bowel is often evacuated and in the dog vomiting is common.- The respiration is at first rapid and deep, and later slow and dyspnceic, the heart is weak and slow, and the pupil is contracted to a small point. These symptoms become more marked as more of the poison reaches the blood, until the respira- tion ceases. In cats these symptoms of depression and paralysis are pre- ceded by a stage of increased movement and evident anxiety, but the later symptoms resemble those in the dog. In man physostigmine elicits practically the same results as in the dog, vomiting and pain in the stomach region, dyspnoea, giddiness and muscular weakness, contrac- tion of the pupil, salivation and perspiration. The heart is slow, muscular twitching may be present and complete collapse follows. In frogs the voluntary movements disappear soon after the injection of physostigmine, the respiration ceases, and last of all the reflexes are paralyzed. Action. Many of these symptoms evidently arise from depression of the Central Nervous System, and the cause of death is the failure of the respiration from paralysis of the medullary centre. Some doubt exists as to what parts of the nervous system first undergo depression. Thus according to Harnack and Witkowsky, the higher centres are weakened earlier than the lower ones, but in man at any rate, the consciousness remains unimpaired after grave derangement of the respiration has manifested itself and after the muscular power is con- siderably depressed. This would indicate that some of the higher cerebral areas preserve their functions after others have been weakened, and several authors have therefore maintained that the depression commences in the cord and medulla oblongata, and only spreads to the cerebrum after large doses. Another unsettled question is whether the stage of depression is preceded by one of direct stimulation of the nervous centres. Some symptoms un- doubtedly point to an increase in their irritability ; for example the increased respiratory movements, and to some extent the changes in the blood-pressure can scarcely be explained save by stimulation, direct or indirect. Further evidence of the stimulant action of physostigmine on the central nervous system has been offered by its effects in epileptics, in whom the number and intensity of the seizures are increased by its use. Guinea- pigs rendered epileptic by operative procedures are also said to be more frequently attacked when physostigmine is exhibited, and even in the dog epileptiform convulsions occur occasionally, while in the cat a stage of excitement is a regular precursor of the depression. These symptoms have been explained by some writers as due to stimulation of the central nervous system, but, on the other hand, may be due to the peripheral effects of the poison, such as the constriction of the air passages by contraction of the bronchial muscles. The question as to whether any general stimulation of the central nervous system occurs in physostigmine poisoning must be left open for the present. The muscular twitching seems to be entirely independent of the central nervous system, for it is not prevented by division of the motor nerves. This symptom is not marked in frogs, but may be so devel- oped in mammals as to simulate convulsions, and is due to stimulation 21 322 ORGANIC DRUGS ACTING AFTER ABSORPTION. of the nerve terminations in the muscles, for it is prevented by curara, which paralyzes these. The antagonism between these two alkaloids is mutual, for the paralysis of the motor nerves induced by curara may be removed by physostigmine applied in somewhat large doses, and animals may thus be recovered from quantities of curara which would otherwise prove fatal. The Respiration is at first somewhat accelerated and then becomes slow and weak. The preliminary acceleration was explained by Bezold and Gotz as due to stimulation of the sensory terminations in the lungs, while others regard it as evidence of central stimulation. The subsequent weakness and slowness of the breathing is undoubtedly of central origin, and death follows from the failure of the respiratory centre. The changes in the Circulation require further investigation. Small doses slow the pulse and increase the blood-pressure, while larger are followed by greater slowing of the heart and a fall in the blood-pressure. The slowness of the pulse is due to the poison acting on the heart directly and not to any inhibitory interference, for it occurs after large quantities of atropine. The action of physostig- mine on the inhibitory nerves has never been satisfactorily decided, for according to some authors they are unaffected, while others assert that their irritability is increased, and Arnstein and Sutschinsky even state that the paralyzing effects of atropine may be removed by it. The con- tractions of the mammalian heart are sometimes said to be strengthened by physostigmine, but this is erroneous ; the increased amplitude of the movements mentioned by Hedbom may be due to the slow rhythm. The increased blood-pressure has also been the subject of some dis- cussion. It seems independent, in part at least, of the vaso-motor centre, for it is not prevented by section of the spinal cord or of the splanchnic nerves, operations which prevent impulses from the centre reaching the vessels. It may be partly due to the powerful contrac- | tion of the intestines expelling the blood from the mesenteric area, or I * to direct action on the muscular coats of the arterioles causing con- | I traction and thus narrowing their calibre, or perhaps to both of these, \ * along with some increase in the activity of the vaso-motor centre. The frog's heart beats more slowly after physostigmine, but here the individual contractions are said to be strengthened and prolonged, and there is definite evidence of stimulation of the heart muscle, which is not seen in mammals. If the vagus be stimulated in the frog after physostigmine, it produces slowing but no complete standstill of the heart, because the irritability of the muscle is so much augmented that the inhibitory apparatus can no longer entirely control it. It has been supposed that physostigmine depresses the endings of the inhibitory nerves, but this has been shown to be incorrect. If such a poison as muscarine produces complete standstill, physostigmine removes it, not by inducing depression of the inhibitory apparatus, but by increasing the irritability of the muscle. PHYSOSTIGMINE. 323 The following experiment, which is mainly a repetition of one devised by Harnack, may serve to show the relationship between the effects of a whole series of poisons, which generally present some difficulties to the student. A frog, with brain and spinal cord destroyed, is stretched on a board, and its heart is exposed by the removal of a triangular piece of skin and division of the sternum. The poisons are then applied in succession by injecting them into the lymph sac, and the vagus may be exposed and placed on elec- trodes. The injection of nicotine causes slowing of the heart (Fig. 30, N), followed by a return to the normal rhythm, after which vagus stimulation has no effect, while stimulation of the sinus still slows the heart. (Nicotine first stimu- lates and then paralyzes the ganglia on the course of the inhibitory fibres.) Muscarine now brings the heart to a standstill (Fig. 30, M), through stimu- lation of the terminations of the inhibitory fibres ia the muscle. Physostig- mine restores the heart to feeble rhythmic contractions (Fig. 30, P), through stimulation of the muscular fibres, which leads to a partial loss of control by the inhibitory apparatus. Copper salts or other muscular depressants cause a return of the standstill (Fig. 30, (7), through neutralizing the stimu- lant action of physostigmine, and thus allowing the stimulated inhibitory endings to regain control. Atropine finally induces an almost complete return to the normal rhythm (Fig. 30, A) by paralyzing the terminations of the inhibitory nerves and thus removing the effects of the muscarine. Here there is distinct evidence of an increase in the irritability of the car- diac muscle of the frog after physostigmine, and this is difficult to reconcile with the slow pulsation generally seen when physostigmine is given alone. In the mammalian heart no such evidence of an increase in the muscular irritability has been adduced, and the vagus arrests it as easily as before the administration of the poison ; according to some investigators even more easily. FIG. 30. Tracing of the movements of the frog's ventricle. During systole the lever makes an up-stroke. Z. Normal, N. After nicotine M. After muscarine. P. After physostigmine. C. After a copper Bait. A. After atropine. (See text.) Physostigmine produces powerful contractions of the Stomach and Intestine exactly resembling those elicited by muscarine and pilo- 324 ORGANIC DRUGS ACTING AFTER ABSORPTION. carpine. It differs from these, however, in causing these move- ments after small quantities of atropine, while larger doses of atropine again stop the contractions set up by physostigmine. The Secretions are also increased by physostigmine as by pilocarpine and muscarine, and here again small quantities of atropine do not prevent the action, while larger quantities arrest it. Thus, the saliva, the tears, the perspiration, the mucous secretions and the pancreatic juice are all augmented by physostigmine. Besides the intestine and stomach, a number of other muscular organs are thrown into contraction by physostigmine ureter, bladder, uterus and bronchial muscle. The Intraocular Muscles also undergo contraction, and their movements under physostigmine have been the subject of a large number of investigations and of a good deal of con- troversy. The pupil contracts when physostigmine is employed either locally or internally, and this contraction may be lessened by the sub- sequent application of atropine, but is not altogether removed except by large quantities. On the other hand, the dilatation of the pupil produced by small quantities of atropine may be diminished by physos- tigmine, but the resulting contraction is much less than that caused by physostigmine applied to the normal eye. The ciliary muscle is acted on in the same way as the pupil, so that the eye becomes accom- modated for near distance, and atropine induces the same modifica- tions., The effects of physostigmine, then, on the intestine, secretory organs, pupil and ciliary muscle are strictly analogous, and are gen- erally attributed to the alkaloid stimulating the terminations of the nerves in these organs. 1 It therefore resembles pilocarpine and mus- carine but its antagonism to atropine is much more complete, and a renewal of the secretion or contraction after atropine can be elicited much more easily by physostigmine than by muscarine or pilocarpine. The intraocular pressure is considerably reduced by the application of physostigmine to the eye and this has generally been attributed to the contraction of the pupil facilitating the escape of the fluid by allowing it freer access to the spaces of Fontana. But the latest writer on the subject, Gronholm, states that it is due to a contraction of the intra- ocular vessels, which lessens the secretion. Physostigmine is Excreted in the urine mainly, appearing in it a few minutes after its injection. It has also been found in the saliva and bile. The symptoms of poisoning with Calabar bean are identical with those caused by physostigmine, except when an old preparation con- taining calabarine is used, when some stimulation of the spinal cord may be induced. PREPARATIONS. Physostigma (U. S. P.), Physostigmatis Semina (B. P.), Calabar or Or- deal bean, the seeds of Physostigma venenosum. Extractum Physostigmatis (U. S. P., B. P.), 0.015-0.06 G. (J-l gr.). Another theory formulated by Harnack Js Jhat, while atropine acts on the termina- tions of the nerves in these organs, physostigmine acts upon the organs themselves on the secretory cells of the glands and on the muscle fibres of the intestine, pupil, etc. PHYSOSTIGMINE. 325 Tinctura Physostigmatis (U. S. P.), 1-3 c.c. (15-45 mins.). PHYSOSTIGMINE SALICYLAS, eserine salicylate (U. S. P.), 0.003 G. ( 2 V gr-)- PHYSOSTIGMINJE SULPHAS, eserine sulphate (U. S. P., B. P.), 0.001-0.003 Lamellse Physostigminse (B. P.), each containing ^Q-Q gr. of physostigmine sulphate. The sulphate and salicylate of physostigmine are colorless or faintly yel- low crystals, without odor, but possessing a bitter taste. The sulphate is deliquescent in the air and is very soluble in both alcohol and water. The salicylate is not deliquescent, has usually a slight acid reaction, and is solu- ble in 150 parts of cold, or 30 parts of boiling water. Both salts undergo decomposition when kept in solution and then assume a reddish-brown color ; the addition of boric or sulphurous acid to the solution is said to retard this decomposition. Preparations of the crude drug also lose their activity when kept for some time, but these are very seldom prescribed. Therapeutic Uses. Physostigmine has been used for its depressant action on the central nervous system in cases of abnormal excitability of the cerebral cortex. In epilepsy and chorea it has received a fairly extensive trial, but has proved of little or no service in most cases, and is positively deleterious in some. The results in the treatment with it of other diseases of the central nervous system, such as tetanus, have been no more favorable, so that it has fallen into disuse. In recent years physostigmine has been given in pills or hypo- dermically in cases of atony of the intestine leading to tym- panitis and meteorism. But it is chiefly used for its action on the intraocular muscles and tension. For this purpose a solution of J-l per cent, is dropped in the eye, 2-4 drops at a time, or small discs of gelatin impregnated with the alkaloid may be applied to the conjunc- tiva (B. P.). The pupil begins to contract in 5-15 minutes, and at- tains its smallest size in half an hour. It remains contracted 12-14 hours, and according to some observers a difference in the size of the two pupils may be made out for several days. The ciliary muscle contracts along with the iris, and the eye becomes accommodated for short distances. This action on the accommodation passes off in 2-4 hours, but the sight is often rendered indistinct for some hours longer by alternate contraction and relaxation of the ciliary muscle. The action of physostigmine on the eye differs from that of muscarine for the former acts more on the pupil, the latter on the ciliary muscle, and the pupil is often contracted by physostigmine while the accom- modation is practically unchanged. The intraocular pressure is some- what increased at first and subsequently sinks. Its action in narrow- ing the pupil after atropine has been made use of to remove the dilation produced so frequently in ophthalmic surgery, but some newer tropeines, which produce a shorter mydriasis than atropine, have almost driven it from this field. It antagonizes the dilatation of the pupil after homatropine and cocaine much more successfully than that due to atropine. It has also been used in cases of synechia (attachment of the iris to the lens) alternately with atropine. The alternate contrac- tion and dilatation of the pupil would, it was hoped, break down the attachment, but the condition is now generally treated by operation. 326 ORGANIC DRUGS ACTING AFTER ABSORPTION. Physostigmine is now chiefly employed to reduce the intraocular pressure in glaucoma. Physostigmine Poisoning has occurred only from eating the bean as yet, and is to be treated by the usual methods of evacuation of the stomach and other general measures. It has been found by Fraser that atropine acts as an antidote to physostigmine in animals, and it might be tried in cases of poisoning. The foil dose of atropine is required. BIBLIOGRAPHY. Fraser. Edinburgh Medical Journal, ix., p. 36, 1864. Journal of Anat. and Physiol., 1867, p. 323. Practitioner, iv., p. 65. Bezoldu. Gotz. Centralbl. f. d. med. Wissenschaft, 1867, p. 241. Arnsteinu. Sustschinsky. Untersucli. a. d. physiol. Laborator. zu Wiirzburg, ii., p. 81. Rogoiu. Ztschr. f. rationelle Heilkunde, xxix., p. 1. Heidenhain. Pfl tiger's Arch. f. Physiol., v., p. 309. Laschkewich. Virchow's Archiv, xxxv., p. 291. Harnack u. Witkowski. Arch. f. exp. Path. u. Pharm., v., p. 401. Harnack u. Meyer. Ibid., xii., p. 366. Turtschaninow. Ibid., xxxiv., p. 208. Schweder. Inaugural Dissertat., Dorpat, 1889. Hedbom. Skandinav. Arch. f. Physiol., viii. , p. 209. Schultz. Arch. f. [Anat. u.] Phys., 1898, p. 66. Rothberger. Pfl tiger's Arch., Ixxxvii., p. 117. Grilnholm. Arch. f. Ophthalmol., xlix., p. 620. Resume. A number of the groups of alkaloids discussed up to this point act on the same peripheral organs and generally present some diffi- culty to the student, so that a few general remarks regarding them may be of service. These drugs acts at two distinct points the peripheral ganglia and the terminations of the nerves in the muscular or glandu- lar tissues. Xicotine, curara and coniine affect the ganglia (Fig. 31, N) ; muscarine, pilocarpine, physostigmine and atropine the termina- tions in the organs (J/, Fig. 31). Curara, coniine and atropine are purely depressant in their peripheral action ; nicotine is first stimulant and subsequently depressant, while muscarine, pilocarpine and physos- tigmine are practically purely stimulant. The action on the ganglia is quite independent of that on the nerve ends, and either may be stimu- lated or depressed after the others have been paralyzed. If, however, the nerve ends be paralyzed (Fig. 31, 2) as by atropine, changes in the ganglia will have no apparent effect, as the impulses arising from their stimulation are blocked in the nerve ends, and, on the other hand, their paralysis does not cause any further retardation of centrifugal im- pulses which are completely blocked already. After paralysis of the ganglia (Fig. 31, 3) the stimulation of the nerve ends is followed by the usual symptoms, because the impulses pass from the nerve ends to the epithelium directly without the intervention of the ganglia. Thus muscarine, pilocarpine and physostigmine act after the paralysis of the ganglia by nicotine or coniine. If the ganglia be paralyzed first, the paralysis of the nerve ends by atropine is followed by no change unless the latter have been in a state of activity. While it is universally acknowledged that atropine arrests the action of muscarine and pilo- carpine by paralyzing the points at which these unfold their action, RESUME, 327 FIG. 31. the subsequent stimulation of the paralyzed terminations by further administrations of muscarine or pilocarpine is by no means so generally believed. The statement that a paralyzed organ cannot be further stimulated seems to have assumed almost the authority of a theological dogma, although numerous points not only in the peripheral action of these drugs, but also in that of others on the central nervous system cannot be easily explained ex- cept on the opposite assumption. Some of the difficulties confront- ing the advocates of this theory have been already mentioned, and others will be met with in the course of this work. If it be granted that a paralyzed tissue may be restored by the action of stimulant drugs, the action of the foregoing alkaloids is much sim- plified. Thus atropine paralyzes the nerve terminations, but these may be restored to activity by very large quantities of muscarine or pilocarpine, unless the quan- tity of atropine given has been too large. The quantity of physostigmine required to re- store them is much smaller than that of pilocarpine, and its ap- plication is therefore much more successful in reinstating the con- dition of active stimulation. These differences between pilo- carpine and physostigmine may perhaps be explained on the analogy of the chemical theory of mass action ; the " affinity " of atropine for the nerve endings is then greater than that of any of the other alkaloids under dis- cussion, that of physostigmine next, and that of pilocarpine and muscariue least. The last mentioned are therefore expelled from their combination with the protoplasm by very small quantities of atropine, and have to be given in very large quantities to remove the atropine from its combination. On the other hand, the attraction of physostigmine for the nerve ends seems much greater ; larger quantities of atropine are required to dis- place it, and smaller quantities of physostigmine restore the activity of the nerve ends. Diagram of a nerve fibre supplying a secretory gland. X, terminations of the cerebrospinal nerve round a ganglion cell. J/ the termina- tions in the epithelium of the sympathetic fibre from the ganglion cell. In 1 the connection be- tween the central nervous system and the secre- tory cells is intact, and secretion may be induced by impulses from the centres, by stimulation at N or at M. In 2 all connection between the nerve and the epithelium is broken off, and se- cretion can be induced only by stimulation of the secretory cells or by restoring the connec- tion. In 3 the connection is interrupted in the ganglion, and secretion can be caused only by drugs acting directly on the epithelium of on the terminations J/. 328 ORGANIC DRUGS ACTING AFTER ABSORPTION. XVI. ACONITINE. This series embraces a number of alkaloids, which resemble each other so closely in their chemical and pharmacological properties as to allow of their being treated together. Some of them which were formerly believed to be perfectly distinct, are now said to be identical, and it is not improbable that future investigation will still further reduce the numbers of the group. These alkaloids are found in a number of species of the Aconitum genus, the best known of which are Aconitum Napellus containing Aeonitine (C^H^NO^ or C 34 H 47 NO U ), Aconitum ferox, Pseudaconitine (C 36 H 49 NO 12 ), and Aconitum Japonicum, Japaconitine (C 34 H 49 NO n ). When aqueous solutions of these alkaloids are heated, they are broken up into one or more acids and simpler bases, so that they may be classed with those of the atropine and cocaine series, which are similarly decomposed. Aeonitine forms acetic acid and Benzaconine (or picroaconitine), which may again be broken down into benzoic acid and Aconine, so that aconitine is acetyl-benzoyl-aconine. Pseudaconi- tine forms Pseudaconine, and Japaconitine Japaconine in the same way. These decomposition products are found in the plant and in the ordi- nary preparations, and in many of the commercial " aconi tines " benzaconine and aconine occur in varying proportions, so that their toxicity varies very considerably. Another alkaloid which resembles aconitine closely in its pharma- cological action, but which is less known, is Delphinine. It is found in stavesacre (Dephinium Staphisagria), along with a number of other bases, which may be the products of its decomposition. The symptoms caused by aconitine, pseudaconitine, Japaconitine, and delphinine are very similar, differing mainly in degree and not in kind. Pseudaconitine is more poisonous than Japaconitine which in turn is slightly more active than aconitine. Delphinine is much less poi- sonous. Symptoms. After very large quantities of aconitine death may re- sult instantaneously, apparently from simultaneous failure of the heart and central nervous system. If smaller quantities be swallowed there is noted, after the ordinary bitter taste of the alkaloid, a feeling of warmth in the mouth and throat, which, agreeable at first, soon becomes prickling and tingling, and extends to the stomach and eventually to the skin. This is ac- companied by a profuse flow of saliva, and often by vomiting. The pulse is very slow, and may be irregular, and later becomes weak and imperceptible, when symptoms of collapse appear. The respiration is slow and labored, and great muscular weakness is complained of. After a time the smarting and tingling of the skin are no longer felt, and on examination the cutaneous sensibility is found to be much re- duced. The intelligence remains unimpaired to the last in many cases, although unconsciousness sometimes occurs, and death is generally, AGONITINE. 329 but not invariably, preceded by convulsions. The pupil is unaffected except when convulsions supervene, when it is dilated. The prickling of the throat and skin is the most characteristic symptom, and is practically diagnostic in cases of poisoning, 110 other drug excepting veratrine having this effect. Death is due to paralysis of the respira- tory centre from the direct action of the poison, although this may be aided by anaemia of the medulla from the imperfect circulation. In small doses aconitine induces slowing of the heart and slight muscular weakness, which is often accompanied by tingling of the lips, tongue and throat. Action. -The prickling, tingling sensation is due to an affection of the Terminal Organs of the Sensory Nerves, as is shown by its appearing first at the point of application of the drug. Thus, when aconitine is swallowed the prickling and warmth is felt in the lips, tongue, and throat, and after small doses may be confined to these parts, while if an ointment containing aconitine be rubbed on the skin, the same sen- sation is induced locally. But no redness or swelling of the skin is induced, nor are blisters formed, so that aconitine differs entirely from the class of skin irritants (page 78). It evidently acts by stimulat- ing the terminations of the sensory nerves, more especially those of common sensation, while the other sensory end organs have not been shown to be involved. Thus, apart from the bitter taste which it possesses in common with all alkaloids, aconitine has no effect upon the taste organs during this stage. The stimulation afterwards passes into depression, which induces a sense of numbness at the point of applica- tion, and in cases of poisoning, in all the surfaces of the body. The taste nerves seem to be involved in this effect, if Laborde's statement be correct that sweet substances have no taste after aconitine. The irritation of the sensory terminations often causes a number of reflexes, such as sneezing, coughing, increased secretion of saliva and vomiting, although some of these may be due in part to stimulation of the medullary centres. Evidence of the stimulation of Other Terminations is presented in fibrillary twitching of the muscles in the frog and sometimes in mammals. This is prevented by curara, but not by section of the nerves, and is therefore attributed to stimulation of the terminations of the motor nerves in muscles. The muscles themselves are comparatively little affected. Waller states that even minute quantities of aconitine abolish the irritability of nerve fibres when it is directly applied to them. The effects of aconitine on the Circulation are somewhat complex, as the heart is affected directly by it, as well as through its inhibitory nerves, and the vaso-motor centre is stimulated in addition. The frog's heart is first accelerated from the direct action of the poison, but this soon passes into the slow pulse and prolonged diastole which are characteristic of inhibitory action. The subsequent standstill may at first be removed by atropine, but somewhat later this remedy fails, as the drug begins to act directly on the heart. A second acceleration may be thus induced, but the contractions soon become irregular, and 330 ORGANIC DRUGS ACTING AFTER ABSORPTION. groups of almost normal beats alternate with peristaltic movements which fail to expel any blood from the heart. Later, the larg^ contrac- tions may alternate with periods of complete quiescence in the ventricle, while the auricles continue to beat, and stimulation of the accelerans nerve is followed by periods of regular contraction. The heart muscle seems to have lost in great part its power of conducting impulses, so that the contraction of the auricle often fails to excite a ventricular systole ; but if the conductivity be increased by stimulation of the accelerator nerve, or if the ventricle be excited by a series of electric shocks, it responds by rhythmical contractions. In mammals, the preliminary quickening of the heart is masked by the strong stimulation of the vagus centre. This produces marked slowing of the pulse, an increased dilation in diastole and a lessened systolic contraction; the amount of blood leaving the heart is consider- ably reduced and the circulation is slackened. These symptoms are the only ones seen in the heart except With very large doses of the drug. They are shown to be due to the action on the inhibitory centres in the medulla by the fact that section of the vagus brings the heart back to its normal rate and extent of contraction. In medicinal doses, then,| 4 the only effect of aconitine on the heart is due to the vagus stimulation,! ? the direct cardiac action not coming into play, and the administration! I of aconite in therapeutics is one of the best methods of eliciting pure^ and unmixed inhibition. In fatal doses, aconitine exerts a further action on the heart, how- ever, for the direct muscular action now comes into play and the heart suddenly accelerates from the slow vagus rhythm to one far above the normal. At the same time it becomes irregular, with a tendency towards the formation of groups of imperfect contractions and of con- tractions originating in the ventricles independently of the auricles. As the action becomes more intense, the irregularity increases, and eventu- ally the heart passes into delirium. A curious fact has been noted by several observers that after section or paralysis of the vagus, a much larger quantity of aconitine is required to produce the acceleration and final delirium than when the nerves are intact. It has generally been stated that the cause of the acceleration is paralysis of the vagus termi- nations, but besides this there is evidently strong stimulation of the cardiac muscle, for the acceleration occurs after division of the vagi and even in the excised heart. The auriculo-ventricular rhythm is disturbed, the auricle often beating at a different rate from the ven- tricle, and the alternate consonance and dissonance of their contractions partly explains the variations in the ventricular rhythm and strength. The blood-pressure in mammals falls rapidly from the lessened out- put of the heart in the stage of vagus stimulation. There is some evidence of an action on some part of the vaso-motor mechanism as well, for some observers have noted a rise in arterial pressure after aconitine in animals in which the vagi had been divided or paralyzed before the exhibition of the drug. The fact that the vagus centre is so strongly stimulated would also suggest the probability of some increase ACONITINE. 331 in the activity of the vase-motor area. After the stage of acceleration has set in, the blood-pressure becomes extremely irregular, alternately sinking to zero and remaining at tlfat point for some seconds and again attaining a fair height. These variations are evidently due to the alternations in the heart's movements. The vaso-motor centre seems eventually to become paralyzed, for it has been found that stimulation of an afferent nerve produced no change in the tension, while stimula- tion of the efferent vaso-motor nerves still caused a marked increase. The vaso-motor nerves and their terminations in the periphery seem to be unaffected by this poison. The Respiration is early affected by acouitine ; it becomes much slower, the movements are more labored than normally, and the ani- mal suffers from marked dyspnoea. The accessory respiratory muscles contract vigorously, and the movements of the abdominal expiratory muscles are so powerful as to suggest the movements of vomiting rather than of respiration. In fatal cases the respiration soon be- comes interrupted by convulsions, and in the intervals between these becomes weaker and eventually ceases. Various explanations of the respiratory phenomena have been given. It is certainly not due to action on the phrenic terminations, for the diaphragm contracts on electrical stimulation of these nerves after its spontaneous movements have ceased. The dyspnoea resembles somewhat that seen on stimu- lation of the centripetal fibres of the vagus, and the theory has been propounded that aconitine stimulates the vagus terminations in the lungs in the same way as the sensory terminations in the skin. The same dyspnoea is seen, however, when aconite is given after section of the vagi, so that it seems to be due to some action on the respiratory centre. The action of aconitine on the Central Nervous System is still a matter of dispute, as the effects on the peripheral nerve-ends tend to obscure the symptoms, but there can be no doubt that certain parts are stimulated. Thus, the vagus centre is undoubtedly thrown into a con- dition of increased irritability, for inhibition of the heart is a marked feature of the action. Probably the vaso-constrictor centre also under- goes some stimulation, and the vomiting so often seen may be caused, at least in part, by increased irritability of the medullary centres. The convulsions seen in both cold- and warm-blooded animals also point to central stimulation, and the respiratory symptoms are certainly of central origin, though their explanation is still unknown. The higher centres seem to be almost unaffected by the drug, for conscious- ness has often remained to the end, and when this is not the case, the mental symptoms are to be ascribed to the changes in the heart and respiration. The stimulation produced by aconitine is therefore con- fined to some of the lower divisions of the central nervous system more particularly to the medulla oblongata. Some authors suppose that the paralyzing action which succeeds the stimulation, is more marked in the sensory than in the motor sphere and as evidence of this it has been pointed out that in frogs the reflexes disappear before the 332 ORGANIC DRUGS ACTING AFTER ABSORPTION. voluntary movements, but this is explained by the anaesthetic action of aconitine on the skin and cannot be accepted as evidence. The paralysis advances much more rapidly in the respiratory centre than elsewhere and death occurs from asphyxia, while the rest of the central nervous system is shown to be still irritable by the occurrence of convulsions. The muscular weakness often complained of after comparatively small quantities may be due to the depression of the circulation through the inhibitory action, or to nausea. The Secretion of saliva is greatly increased by aconitine from the irritation of the sensory terminations in the mouth and from the nausea. The cold perspiration observed in poisoning may be ascribed to the collapse rather than to any direct action on the sweat glands, although Aubert states that aconitine is a powerful diaphoretic in itself. Acouitine causes a marked fall of Temperature both in fever and in normal animals, but the precise way in which this action is elicited is unknown. Brunton and Cash found that after aconite the temperature fell more rapidly than usual if the animal was kept in a cool bath, but rose more readily if it was subjected to external warmth. The fall in temperature is generally ascribed to the depression of the circulation from the inhibitory action, but this observation would seem to indicate that aconite also acts upon the centres regulating the temperature of the body. In cases of Poisoning in animals atropine has been found to alleviate the symptoms and not infrequently to lead to recovery after doses which would otherwise have been fatal. This improvement is more espe- cially marked in the respiration which may resume its normal charac- ter and persist until heart paralysis sets in. Boehm explained this by a supposed action on the terminations of the vagus in the lung, but it is more probably to be ascribed to the stimulant action of atropine on the respiratory centre. In those cases the cause of death is said to be cardiac paralysis, but the stage of irregularity and the final delirium cordis is certainly retarded very considerably by atropine. Atropine appears to be the antidote from which most is to be hoped for in cases of aconite poisoning. Aconitine is Excreted mainly by the urine. Minute quantities have also been found in the saliva and bile. Benzaconine is very much less poisonous than aconitine and, in fact, can scarcely be included among active poisons, though very large quantities act on the heart, slowing it and rendering it irregular, and also depress the respiration . It has no effect on the sensory terminations. Aconine itself is almost inactive, but large quantities strengthen the heart beat and paralyze the terminations of the motor nerves like curara. It seems unlikely that these alkaloids have any influence on the action of the aconite preparations, although the possibility cannot be excluded at present. The alkaloids obtained from some other species of Aconitum have been found to differ considerably from aconitine and pseudaconitine in their ac- tion. In Aconitum septentrional e three bases lappaconitine, septentrionaline and cynoctonine have been discovered. Lappaconitine causes clonic convul- sions, vomiting, dyspnoaa and finally paralysis of the respiration and heart, ACONITINE. 333 aiid in the frog lessens the sensibility of the skin. Septentrionaline does not cause poisoning when taken internally, but injected subcutaneously induces local anaesthesia and later paralysis of the motor terminations like curara. Cynoctouine is also inactive when swallowed and is less poisonous than the others when applied by hypodermic injection when it causes tonic and clonic convulsions which are not generally followed by paralysis. Two alkaloids, lycaconitine and myoctonine, have been found in Aconitum lycocto- num, and induce almost identical symptoms. They increase the reflex excitability, and this is followed by convulsions and later by paralysis of the terminations of the motor nerves and by failure of the heart. PREPARATIONS. Aconitum (U. S. P.), Aconiti Radix (B. P.), the root of Aconitum Na- pellus, monk's-hood. TINCTURA ACONITI (U. S. P.), 1-5 drops every 1-3 hours. TINCTURA ACONITI (B. P.), 5-15 mins. If frequently repeated, 2-5 mins. Fluidextractum Aconiti (U. S. P.), 0.05-0.1 c.c. (1-2 mins.). Linimentum Aconiti (B. P.). Aconitina (U. S. P., B. P.), an alkaloid obtained from aconite root. It is almost insoluble in water but is freely soluble in alcohol. Commercial aconitine very often contains large amounts of aconine and benzaconine, and therefore varies considerably in activity. Unguentum Aconitino3 (B. P.), 2 per cent. Staphisagria (U. S. P.), Staphisagriae Semina (B. P.), the dried ripe seeds of Delphinium staphisagria, stavesacre. Fluidextractum Staphisagrice, 0.05 c.c. (1 min.). Unguentum Staphisagrice, (B. P.). Therapeutic Uses. Aconite is employed to a considerable extent in England, the United States and France, while it has fallen into disuse in some other countries. Its pharmacological action suggests its use to slow and weaken the heart and circulation, to lower the temperature and to benumb the terminations of the sensory nerves in the skin. Digitalis is often prescribed to slow the pulse, but it has other effects on the heart and circulation, and where these are not indicated, aconite may well be used. Both drugs slow the pulse in the same way, but while aconite slackens the circulation and lowers the blood-pressure, digitalis accelerates the blood current and increases the arterial tension. The temperature is also reduced by aconite, but the newer antipy- retics have supplanted it for this purpose, as they are more certain and more powerful in their effects. The tincture is still prescribed how- ever, and ought to be given in small repeated doses. When fever is attended by a very quick pulse, aconite is especially likely to be of service, but it ought to be avoided when the heart is very weak. The action of aconitine on the sensory nerve terminations has been taken advantage of in cases of neuralgia, and there is decidedly much more reason for its use than for that of the great majority of drugs reputed to be beneficial in this condition. Either the tincture, or a 2 per cent, solution of the alkaloid in oil, or the ointment of the B. P. may be employed externally. Aconitine has also been injected sub- cutaneously (Y^-JO- m g-) ' in neuralgia, but this mode of application is not to be recommended, as it causes very severe pain, which in some 334 ORGANIC DRUGS ACTING AFTER ABSORPTION. cases lasts a long time. The internal administration of aconite in neuralgia does not seem to be followed by any improvement. Staves- acre is scarcely used in medicine at present. BIBLIOGRAPHY. Liegeois et Hottot. Journ. dela Physiol., 1861, iv., p. 520. Pluyye. Virchow's Arch., Ixxxvii., p. 410. Ringer and Murrell. Journ. of Physiol., i., p. 232. Boehm u. Wartmann. Verhandl. d. phys.-med. Gesellsch. zu Wiirzburg, 1872, p. 63. Eu-erx. Arch. f. exp. Path. u. Pharm., i., p. 385. Anrep. Arch. f. [Anat. u.] Phys., 1880. Supplemen., p. 161. Lubbe. Inaug. Diss., Dorpat, 1890. Dohrmann. Inaug. Diss., Dorpat, 1888. Rosendahl. Arb. a. d. pharmak. Instit. Dorpat, xi., p. 1 (very complete bibliography up to 1895). Matthews. Journ. of Exp. Med., ii., p. 593. Cash and Dimstan. Transactions of the Royal Society, cxc., p. 239 ; ccviii., p. 39, and ccix., p. 97. Schiller. Arch. f. Anat. u. Phys., 1904, p. 248. (Delphinine. ) XVII. VERATRINE. Several species of the genus Veratrum have been found to contain alkaloids, the most important of which resemble each other in many respects, and also present many points of analogy to those of the preceding group. The chief members of this series are Veratrine (cevadine) and Proto- veratrine, the former of which is found in Veratrum Sabadilla (Asagrsea officinalis or Schoenocaulon officinale), cevadilla, and in Veratrum viride, Green Hellebore, 1 while the latter is the chief active principle of Veratrum album, White Hellebore. 1 Each of these alkaloids is accompanied by a number of others, most of which are entirely inactive, while several of them are only weak poisons and possess little interest. In cevadilla, in addition to Veratrine, there are found Cevadilline, Sabadine, Sabadinine and another base, which is known as the Veratrine of Wright or Couerbe. In white hellebore Protoveratrine is accompanied by Jervine, Pseudojervine, Rubijervine, Protoveratridine and others. Green hellebore contains a little Verairine along w r ith Jervine, Pseu- dojervine and Rubijervine. Jervine, Sabadine and Sabadinine are known to possess some action on the organism ; cevadilline and Wright's veratrme have not been examined, while the others are said to be inactive. Veratrine (C 32 H 49 NO ) and protoveratine (C ?2 H 51 NO n ) are both powerful alkaloids, the latter almost rivaling aconitine in its toxicity. Veratrine can be decomposed into angelic acid and a base, cevine, which seems to be nearly related to aconine. Protoveratine is prob- ably a combination of isobutyric acid and a similar base. Veratrine occurs in two forms, one crystalline, the other amorphous ; the one passes easily into the other, and their effects are identical in animals. 1 Hellebore is also the popular name of Helleborus niger, which differs entirely from Veratrum in its principles and also in its action. VEEATRINE. 335 The effects of veratrine on the central nervous system and the sen- sory terminations resemble those of aconitine very closely. On the other hand the muscles present a curious reaction to veratrine, which is entirely absent in aconitine poisoning. Symptoms. The symptoms in man and other mammals commence with prickling and burning in the mouth followed by a sensa- tion of warmth in the stomach, marked salivation, nausea, and vomiting. The bowel is more involved in the effects, than is the case in aconitine poisoning, for violent purging accompanied by severe colic is a common symptom. The prickling sensation soon spreads from the mouth and throat to the skin, and is generally followed by profuse per- spiration. The pulse becomes slow and irregular, the respirations slow and labored. Fibrillary contractions of the muscles and convul- sions are generally observed, and after some time collapse sets in and is followed by unconsciousness and eventually by respiratory failure. Action. When veratrine is applied in ointment to the Skin the same prickling, warm sensation may be elicited locally, and some of the poison is absorbed, as is shown by these symptoms sometimes occur- ring in other parts of the body. The cause of this is, as in the case of aconite, stimulation of the terminations of the sensory nerves. This action causes violent sneezing and coughing when small quantities of veratrine come in contact with the sensitive mucous membranes of the nose and throat and the Sabadilla is therefore known popularly in Germany as Nieswurz (Sneeze-wort). After the irritant action has lasted for some time, the sensory terminations in the skin become less sensitive, and a feeling of numbness and of cold is noted. Protovera- trine seems to cause less irritation of the sensory terminations than veratrine, and the subsequent local anaesthesia is more complete. The Terminations of the Motor Nerves are paralyzed in the frog by large quantities of veratrine, but this paralysis is not preceded by an increase in their irritability, as was formerly supposed. The Nausea and Vomiting which are invariably present in veratrine poisoning, may be due in part to the irritation of the sensory termina- tions of the stomach, but must probably be attributed for the chief part to central action. The salivation may be merely secondary to this emetic effect, or the poison may act on the salivary gland di- rectly. Nothing is known with certainty regarding the cause of the Purgation, but it is presumably induced by some action on the nervous mechanism of the intestine. The profuse Perspiration which follows the injection of large quantities of veratrine, and the cutaneous secre- tion noted in the frog, have been attributed to stimulation of the ter- minations of the nerves regulating the activity of the glands. The most characteristic action of veratrine, however, is that on the Striated Muscles. If a small quantity be injected into the lymph-sac of a frog a curious clumsiness and awkwardness in the movements becomes apparent, and after a few minutes it is evident that this is due to inability to relax its muscles. When a muscle is exposed, it is seen to contract as rapidly as usual, but instead of immediately relax- 336 ORGANIC DRUGS ACTING AFTER ABSORPTION. ing again, it remains shortened and offers resistance to the contraction of the opposing muscles. The animal can no longer coordinate its movements therefore ; for example, it can no longer extend a limb FIG. 32. sive contractions taken at intervals of one minute, five minutes after the injection of veratrine. The contraction is higher and much more prolonged than in a, and the lever returns very slowly to the base line. immediately after flexing it, as it does ordinarily in crawling, and loco- motion becomes very slow and ungainly. This characteristic action is most easily seen on comparing the tracings obtained from a muscle stimulated directly by single induction shocks before and after the application of veratrine (Fig. 32). In the first part of the tracing it will be observed that the height of the con- traction is increased by veratrine, but this feature sinks into the back- ground before the marked prolongation of the second part of the curve. Instead of the almost instantaneous return to the base line seen in the normal tracing, the curve shows generally a slight undulation, and then a very slow fall, the period of relaxation generally being 20-30 times as long as that in the unpoisoned muscle, and the whole contraction lasting 5-10 seconds in favorable circumstances. If, however, the muscle be stimulated repeatedly at short intervals, so as to induce fatigue, the length of the curve decreases until it cannot be distin- guished from the ordinary muscle tracing ; a similar effect is produced by subjecting it to cold, or by heating it beyond a certain point, while moderate heat increases the abnormalities of the tracing. If an un- poisoned muscle be stimulated repeatedly, so as to induce fatigue, and veratrine be then injected, it is found that a marked improvement in the contraction occurs, so that while fatigue lessens the prolongation of the veratrine curve, veratrine removes to some extent the effect of fatigue. In the prolonged contraction more energy is used up than usual, and the amount of heat formed during muscular contraction is therefore increased by veratrine. Besides the alterations seen in the tracing, veratrine increases the irritability and absolute strength, so VERATRINE. 337 that the muscle reacts to weaker stimuli and contracts against a greater weight than usual. The muscular phenomena are best observed in the frog, but can also be elicited in warm-blooded animals, although in the latter they do not play such an important role in the symptoms of poisoning. In the frog, the muscle is finally paralyzed, but this does not occur in mam- mals, as here the respiratory centre fails long before the quantity of veratrine necessary to induce this effect has been absorbed. The first explanation that suggests itself for the curious muscular phenomena, that they are due to some change in the nervous system, is negatived by the fact that excised muscles show exactly the same reaction. Bezold explained the prolongation by supposing that a change was produced in the muscle substance, by virtue of which a single stimulus was enabled to set up a tetanic contraction ; but this is shown to be incorrect, for if the nerve of another nerve-muscle prepa- ration be laid on the veratrinized muscle, no secondary tetanus is set up in it, as would be the case if the first muscle were undergoing tetanic contraction. The generally accepted view is that veratrine increases the catabolic changes in muscle, and thereby induces a prolongation of the period of active contraction, as well as an increase in the height of contraction and in the absolute strength. Fatigue, by reducing the amount of substance capable of undergoing catabolic change, and cold, by increasing its stability, counteract the effects of veratrine. In the tracing of veratrinized muscle a curious undulation is frequently seen at the top of the contraction, or the ascent may at first be rapid, then slower, and then again more rapid. This has been ascribed to veratrine acting differently on the two forms of muscle fibre, the gray and the red, but this explanation has recently been shown to be erroneous (Carvallo and Weiss). Botazzi supposes that the initial contraction is due to the aniso- tropous substance, while the secondary slower and prolonged contraction is induced by increased activity of the sarcoplasm. The electrical organ of the torpedo is apparently affected by veratrine in the same way as striated muscle. Waller has recently shown that veratrine abolishes the irritability of the peripheral nerves when a solution is applied to them directly. Protoveratrine differs entirely from veratrine in its effects on the muscles and the terminations of the motor nerves. The latter are not paralyzed even by the largest quantities, while the contraction of the muscle is rather shortened than prolonged. The contraction is higher and the absolute strength is increased, but fatigue is induced more readily than in the unpoisoned muscle, so that protoveratrine appears "to increase the muscular force temporarily, but leads to its early ex- haustion. Circulation. The ventricular muscle of the frog's heart is affected by veratrine in very much the same way as the ordinary striated muscle, while the auricular muscle, consisting chiefly of unstriated fibres, is much less altered. The ventricular systole is at first stronger and more prolonged ; somewhat later one part of the ventricle is seen 22 338 ORGANIC DRUGS ACTING AFTER ABSORPTION. to remain contracted during the alternate diastoles of the rest, and waves of contraction spread over the heart resembling the peristaltic movements of the intestine rather than the ordinary contractions of the heart. The whole ventricle is smaller than usual, and but little blood is expelled into the aorta. Still later the persistent contraction spreads over the whole ventricle, so that it dilates only half as often as it did at first, while the auricles maintain their original rhythm. This is evidently due to action on the muscle ; the contraction is so prolonged as to limit the number of diastoles, and the ventricle can therefore react only to every alternate contraction of the auricle. After this " half-rhythm " has persisted for some time, the contractions become slower and weaker, and the heart finally comes to a standstill. The behavior of a frog's heart under veratrine resembles closely that characteristic of the digitalis series. In mammals, the chief circulatory symptoms arise from stimulation of the medullary centres resembling that seen in the earlier stages of aconite poisoning. The stimulation of the cardiac inhibitory centre produces slowing of the heart and a decrease in its output, while at the same time the peripheral vessels are contracted by the increased activity of the vaso-motor centre. After larger quantities the terminations of the vagus are paralyzed, and the vaso-motor centre is at the same time depressed, so that the pulse becomes quicker, but the blood-pressure is somewhat lowered. In the mammalian heart no such prolongation in the systole is seen as in the frog's, but that a slight stimulant action is exercised by veratrine is shown by the fact that very large doses quicken the rhythm even after atropine. Veratrine, therefore, seems to resemble aconitine in its effects on the mammalian circulation, but much larger quantities are required to produce the same effects, and the more evident symptoms of stimulation of the myocardium are not elicited. The Eespiratory Changes under veratrine also resemble those under aconitine, and in both the cause of death is the same paralysis of the respiration. The Central Nervous System seems to undergo stimulation under veratrine as under aconitine. This is evidenced by the convulsions seen in mammals as well as by the stimulation of the medullary centres already noted. After large quantities of the poison this stimulation gives place to paralysis, terminating in failure of the respiration. The highest centres seem less affected than the spinal cord and medulla oblongata, for complete consciousness has remained until immediately before death in several fatal cases. The Temperature is sometimes found lower than the normal after veratrine, probably owing to the slowing of the circulation. In other cases, when the convulsive movements are very marked and the heat production is therefore much increased, the temperature has been found somewhat higher than usual. In cases of poisoning in mammals atropine is said by Lissauer to have some value, probably owing to its action on the respiratory centre and on the vagus terminations in the heart. EMETINE. 339 As regards the other alkaloids of this series, jervine, sabadilline and saba- dinine seem to possess the same action as veratrine, but are much less poison- ous. Protoveratrine, which as has been said, differs from veratrine chiefly in not prolonging the muscular contraction and in the effects on the sensory terminations, is much more poisonous. Its action resembles that of aconitine as much as that of veratrine, and it may therefore be regarded as a link con- necting the two groups. PEEPARATIONS. Veratrina (U. S. P., B. P.), a mixture of alkaloids obtained from the seeds of Asagrsea officinalis (U. S. P.); a mixture of alkaloids prepared from ceva- dilla, the dried, ripe seeds of Schcenocaulon officinale (B. P.), forms a white or gray, amorphous or semi-crystalline powder without odor, but causing in- tense irritation of the nostrils, with an acrid taste and leaving a sensation of tingling and numbness on the tongue. It is insoluble in water but soluble in alcohol. It contains veratrine and the other alkaloids of the plant. Unguentum Veratrinx (U. S. P., B. P.). Oleatum Veratrinse (U. S. P.). Veratrum (U. S. P.), American or Green Hellebore, the rhizome and roots of Veratrum viride. Fluidextractum Veratri, 0.2-0.5 c.c. (36 mins.). Tinctura Veratri, 0.2-0.5 c.c. (3-6 mins.). Therapeutic Uses. The therapeutic uses of the members of this series are extremely limited. Veratrine is used in the form of the oleate or ointment as an external application in cases of neuralgia, and is certainly a safer remedy than aconite. Neither its pharmacological action nor therapeutic experience supplies any indications for its inter- nal use. Yeratrum viride is used internally in the same class of cases as aconite, but as its activity is due to veratrine it might well be dis- carded from the pharmacopeia. Yeratrum album is also a superfluous drug. BIBLIOGRAPHY. Bezold u. Hirt. Untersuch. aus dem phys. Laborat. zu Wiirzburg, i., p. 75. Kolliker. Virchow's Archiv, x., p. 257. Rossbach. Ptiiiger's Archiv, xiii., p. 607. Lissauer. Arch. f. exp. Path. u. Pharm., xxiii., p. 36. Brunton and Cash. Journ. of Physiol., iv., p. 1. Overend. Arch. f. exp. Path. u. Pharm., xxvi., p. 1. Eden. Arch. f. exp. Path. u. Pharm., xxix., p. 440. (Protoveratrine.) Schenk. Pfl tiger's Archiv,. Ixi., p. 494. Santesson. Skand. Arch. f. Phys., xiv., pp. 1, 430. Carvallo etWeiss. Joum. de Phys. et Pathol., i., p. 1. Garten. Pfliiger's Arch., Ixxvii., p. 485. Botazzi. Areh. f. [Anat. u.] Phys., 1901, p. 377. Buchanan. Journ. of Physiol., xxv., p. 137. XVIII. EMETINE (IPECACUANHA). Ipecacuanha (Cephselis Ipecacuanha) has long been used for its emetic and expectorant virtues, and was until recently believed to contain only one alkaloid, Emetine. Paul and Cownley have shown, how- ever, that this so-called principle is really made up of three distinct alkaloids, Cephceline (C 14 H 19 NO 2 ), Emetine (C 14 H 18 (CH S )NO 2 ), and Psychotrirw, the first two of which are quinoline derivatives and pro- 340 ORGANIC DRUGS ACTING AFTER ABSORPTION. duce almost identical effects, while psychotrine is nearly inert. It seems probable that one or both of them are formed by a number of other plants, some of which have been used as emetics in former times, and among which may be mentioned several species of violet. Their chief action is exerted on the alimentary canal, although they are also local irritants. Symptoms and Action. When administered internally emetine has a bitter, acrid^jtaate, and produces a copious, salivary, secretion, fol- lowed later by nausea and vomiting with the usual attendant symp- toms. The drug is generally largely eliminated by vomiting, so that no further effects are observed. When injected hypodermically, however, it induces nausea, vomiting and purging, and blood is fre- quently voided in the stools, a condition of collapse follows, and the animal generally dies of exhaustion in the course of a few hours after the onset of the symptoms. Very large quantities injected subcuta- neously or intravenously may fail to elicit vomiting, but the collapse symptoms appear, and after some weak convulsive movements, the animal dies of cardiac failure. In those cases in which death follows rapidly on the injection, no pathological lesions may be found after death, but in experiments where smaller quantities are injected, and the animal survives for 18-24 hours, the stomach and intestine often ex- hibit the appearances of an acute gastro-enteritis. The mucous mem- brane is swollen, congested and often covered with a muco-purulent secretion or studded with ecchymoses, and in dogs ulceration is often present. A lesion which is not by any means constant, but which occurs in a considerable number of animals and especially in rabbits, is oedema of the lungs. Emetine possesses a gowerfuL Irritant Local Action, which is, how- ever, much more markeOmcertain individuals than in others. The smallest quantity of the powdered root of ipecacuanha is sufficient to induce in the subjects of this idiosyncrasy considerable swelling and injection of the conjunctival and nasal mucous membranes, with salivation, tears, sneezing, coughing and bronchial catarrh. When applied to the skin as a liniment, it produces redness, itching and oc- casionally a pustular eruption, but Lowin states that the alkaloids are devoid of action on the subcutaneous tissues. Its action on the alimentary canal also indicates its irritant properties. It has been much discussed whether the emesis is wholly due to this irritant action on the gastric mucous membrane, or whether emetine, like apomor- phine, has a specific action on the centres in the medulla oblongata con- trolling vomiting. In view of the fact that emetine, like many other irritants when injected subcutaneously, has a specific action on the ali- mentary canal it seems unnecessary to have recourse to any action on the central nervous system, and almost all the facts brought forward as evidence of this supposed central action have been disproved. It is sometimes stated that section of the vagus nerves does not prevent ipecacuanha from causing vomiting, whereas if it only irritated the stomach, the division of these nerves (which are probably the chief sensory nerves of EMETINE. 341 the stomach) ought to prevent it by hindering the impulses reaching the medulla and setting up reflex processes there. But this statement has been contradicted, and no great weight can be laid on the argument in any case, because section of the vagus alone causes violent and persistent vomiting very often. Thumas states that the application of emetine solutions to the medulla provokes vomiting, but this method is so open to objection that his inference that the alkaloid acts on the vomiting centre, can hardly be re- garded as justifiable. On the other hand, it may be urged that if emetine acted on the medullary centre, vomiting ought to follow after smaller doses and more quickly when it is injected subcutaneously, being thus more rapidly absorbed, than when it is taken up from the stomach. But this is not the case, for ipecacuanha causes emesis as soon and in as small quantities when it is administered by the stomach, whereas apomorphine which acts on the centre directly, acts much more rapidly and efficiently when it is injected subcutaneously. While the question cannot be said to be definitely settled, almost all the facts point to peripheral gastric, and not to central action. Emetine injected into a vein weakens the heart's action, and induces a fall of blood-pressure, but when it is injected subcutaneously or given by the mouth the heart is much less affected. In the frog, emetine does not cause vomiting, but a slowly advancing central paralysis follows its injection, the spontaneous movements ceasing early, and later the reflex excitability disappearing. The contractions of the heart are rendered weak and irregular, and eventually cease from paralysis of the cardiac muscle. The striated muscle of the frog has been said to be weakened and paralyzed by emetine, but this has been disputed, and the muscular action is in any case slight and unimportant in frogs poisoned with the alkaloid. The nausea and vomiting are accompanied by the usual symptoms muscular weakness and depression, increased secretion of saliva and of mucus by the glands of the throat and respiratory passages, often per- spiration and generally temporary acceleration of the pulse. (See apomorphine, p. 235.) Most of the researches on which the above statements are based have been performed with a mixture of the alka- loids, but the two chief of these resemble each other very closely in their effects, cephaBline being somewhat more powerful than pure emetine. Emetine and cephseline have not been used in practical therapeutics, various preparations of the crude drug being prescribed instead. Their isolation is so difficult that it seems unlikely that the pure alkaloids will be made use of in the near future, and from a comparison of their effects with that of ipecacuanha it scarcely seems desirable that they should be introduced. For ipecacuanha is much less liable to produce purging than emetine, probably because the solution of the alkaloids is retarded by the presence of large quantities of tannin bodies and other impurities, while at the same time the emetic action is but little slower than that of emetine. PREPARATIONS. U. S. P. Ipecacuanha, the root of Cephselis Ipecacuanha. The powdered root is prescribed in dysentery in quantities of 2-4 G. (30-60 grs.); emetic, 2 G. (30 grs.); expectorant, 0.06-0.3 G. (1-5 grs.). 342 ORGANIC DRUGS ACTING AFTER ABSORPTION. Fluidextractum Ipecacuanhas, expectorant, 0.2-0,5 c.c. (38 mins.); emetic, 2 c.c. (30 mins.). SYRUPUS IPECACUANHA, \ expectorant, 0.1-1 c.c. (2-15 mins.); emetic, VINUM IPECACUANHA, ) 2-4 c.c. (-1 fl. dr.); for a child. TINCTURA IPECACUANHA: ET OPII contains 10 per cent, opium, i. e., is of the same strength as laudanum, 0.3-1 c.c. (5-15 mins.). PULVIS IPECACUANHAS ET OPII (10 per cent, opium), Dover's Powder, 0.3-1 G. (5-15 grs.). B. P. Ipecacuanhas Eadix, the dried root of Psychotria Ipecacuanha, expectorant, J- 2 grs.; emetic, 15-30 grs. Extractum Ipecacuanha Liquidum, expectorant, -2 mins.; emetic, 15-20 mins. Acetum Ipecacuanha?, 10-30 mins. VINUM IPECACUANHA, expectorant, 10-30 mins. ; emetic, 4-6 fl. drs. Trochiscus Ipecacuanha, contains J gr. of the powdered root. TROCHISCUS MORPHIN^E ET IPECACUANHA, each contains ^ gr. of mor- phine hydrochloride. PULVIS IPECACUANHA COMPOSITUS, Dover's Powder, 10 per cent, opium, 5-15 grs. Pilula Ipecacuanha cum Scilla, 4-8 grs. This pill is formed from Dover's Powder, and contains about 5 per cent, of opium. Therapeutic Uses. Ipecacuanha has been largely employed as an emetic, and although it has been replaced for some purposes, notably in cases of poisoning, by apomorphine, it still has a certain field of use- fulness in cases in which an emetic is indicated but in which the hypo- dermic method is objectionable, as in children. At present, ipecacuanha is used chiefly as an expectorant in the treatment of inflammatory conditions of the respiratory passages^ For this purpose it is prescribed in very much less quantities than~those necessary to produce emesis. It acts indirectly through its nauseating properties, and has the ad- vantage that its action is much more prolonged than that of apomor- phine, and at the same time is not so depressant as that of several metallic substances, such as tartar emetic, which are used for the same purpose. It increases the secretion of the bronchial mucous mem- brane, and further tends to render it more fluid, so that the mucus can be coughed up more easily. The increased secretion may also be of service by protecting the inflamed and irritable membrane from the cold air and thereby lessening the cough, and in order to strengthen this ac- tion ipecacuanha may be prescribed in combination with opium, either as a lozenge or in the famous Dover's powder. When the secretion of the bronchi is already excessive, and the cough is rather to be encour- aged than repressed, these preparations are of course contraindicated. Ipecacuanha is also employed as a diaphoretic, either alone or more commonly as Dover's powder. The perspiration is not so copious as that following pilocarpine and other diaphoretics, but resembles rather that produced by warmth applied to the skin. Dover's powder is therefore a common remedy in chills and in commencing catarrh of the resp Ipecacuanha is used very largely in dy^niery^ particularly in tropi- cal dysentery, in which it seems to act almost as a specific. Its effect COLCHICINE. 343 is attributed by some authorities to the large amount of tannin, con- tained in the root, and a preparation of ipecacuanha from which the alkaloids have been removed (Ipecacuanha Deemetinisata) is said to be as valuable in these cases as the unaltered drug. Others are inclined to ascribe some of the virtues of ipecacuanha to the alkaloids, and deny that the same results are obtained by the use of this preparation. The purified powder has the advantage of not causing any nausea or vomit- ing, and is certainly to be preferred to the crude root if the claims of its advocates prove to be well founded. Very large quantities of the powdered root are generally required in dysentery. Many prescribe enough to cause vomiting at first, and then follow this up with smaller quantities which are used along with morphine or ice, or with sina- pisms to lessen the nausea and vomiting. Others give a few drops of laudanum at once, and when the medullary irritability is thus reduced, and there is less danger of vomiting, prescribe 30-60 grs. (2-4 G.) of the powdered root, and continue the treatment with smaller doses. Ipecacuanha has been recommended in very small quantities as a stomachic, even in cases of vomiting, and its action on the mu- cous membrane might be expected to be of value in some cases ; but it very often fails to have any eifect, and is not widely used for this purpose. BIBLIOGRAPHY. Dyce Duckworth. St. Bartholomew Hospital Keports, v., p. 218 ; vii., p. 91. Podwyssotzki. Arch. f. exp. Path. u. Pharm., xi., p. 231. Lowin, Kimura, and Zepf. Arch, internat. de Pharmacodyn., xi., pp. 9, 405; xii., p. 345. Wild. Lancet, 1895, ii., p. 1274. XIX. COLCHICINE. Colchicine and colchicdne are two nearly related bodies found in the seeds and corrn of Colchicum autumnale, which owes its activity to their presence. They are generally included among the alkaloids, but differ from the other members of this class in possessing an acid reac- tion. Their chemical structure is still imperfectly known, but they do not seem to contain a pyridine ring ; colchicine [C r H 9 (OCH 3 ) 3 - (NHCOCH 3 )COOCH 3 ] is the methyl ether of colchiceine [C 15 H 9 - (OCH 3 ) 3 (NHCOCH 3 )COOH] . These two principles are apparently identical in their effects, which are observed chiefly in the alimentary canal. Symptoms. No symptoms whatever follow the use of colchicum in ordinary therapeutic quantities. After the administration of a poison- ous dose to man or animals several hours elapse before any symptoms are elicited, and the amount injected has but little influence on the duration of this preliminary stage. Whether given by mouth or hypo- dermically, colchicine produces symptoms of discomfort in the stomach 344 ORGANIC DRUGS ACTING AFTER ABSORPTION. and intestine. Pain in the gastric region is followed by salivation, nausea, vomiting, and diarrhoea. At first the evacuations are the ordinary contents of the stomach and intestine, but afterwards a quan- tity of sticky mucous fluid may be ejected, often streaked with blood. Later, a condition of depression, apathy and collapse follows, and the movements become slow and difficult, more especially in the posterior extremities, which eventually become completely motionless ; the paralysis then progresses upwards* until the movements of the fore limbs and respiratory muscles are involved, when death occurs from asphyxia. In man, the intelligence remains until death, though there is generally some giddiness and precordial anxiety, and occasionally some confusion or even delirium preceding the collapse. In mammals poisoned with colchicine, the alimentary canal exhibits all the appearances of acute gastro-enteritis, with numerous ecchymoses especially in the upper part of the bowel. In less acute cases these inflammatory symptoms are less marked, and in man there is seldom more than catarrh of the duodenum. The Circulation is but little affected apparently. In animals the blood-pressure and heart rhythm remain normal, and though a small, rapid pulse may be one of the features of the poisoning in man, this is due to the collapse rather than to any direct action on the circula- tory organs. The Respiration is slow, but is deep and full at first. Later it be- comes shallow, and the failure of the centre is the cause of death, the heart continuing to beat for some time afterwards. The Movements of the Bowel are much hastened when the symptoms set in, and Jacobj believes that this is due to an increase in the irrita- bility of the nervous mechanism, which accordingly reacts more strongly than usual to the natural stimuli ; but this is entirely inadequate to explain the acute inflammatory appearances, which are evidently due to an irritant action on the mucous membrane. When Locally Applied to sensitive mucous membranes, or when in- jected hypodermically, colchicine is intensely irritating, producing redness and prickling in the skin, and a burning sensation in the mouth and throat. The Nervous Symptoms are supposed by some to be due to a direct action on the central nervous system, but may probably be ascribed rather to a condition of collapse produced indirectly through the action on the abdominal organs. It is true that in many cases, especially in man, the post-mortem appearances do not indicate any marked alter- ation of the stomach and intestine, but the symptoms throughout in- dicate that the nervous effects are indirect in their origin, and not due to any direct depression of the brain cells. When the collapse symp- toms appear, a certain degree of insensibility to external impulses may be made out in the integument, but this seems due rather to the gen- eral depression than to any real anaesthesia of the skin. The influence of colchicine on the Kidneys varies, for in some cases complete anuria is produced for many hours, while in others the urine COLCHICINE. 345 is slightly increased. The constituents of the urine are not materially altered by ordinary therapeutic doses of colchicum, and, in particular, the uric acid shows no constant change in amount. In animals bloody urine is sometimes passed after colchicine. All of those symptoms are exactly those caused by a large number of poisons, including some of the bacterial toxines and the heavy metals. Many local irritants when injected into the blood or when absorbed from the subcutaneous tissue or the alimentary canal, exercise an immediate, local action, which betrays itself in pain, or ecchymosis and swelling at the point of injection, but these symptoms pass off in a short time and the animal becomes apparently normal for many hours or even days. At the end of this time, however, symptoms be- gin to develop at two points -in the alimentary canal and in the kidneys. The reason probably is that the poisons are excreted at these points and are either freed from some harmless combination in which they have circulated in the tissues, or perhaps collect in larger quantities in the excretory organs. At any rate, irritation and later acute inflammation are set up at these points. At first the irritation excites only diarrhoea and diuresis, but as it goes on gastro-enteritis and anuria or hsematuria may be produced. The symptoms from the intestine and kidney may not be equally well marked ; at one time the one becomes inflamed while the other is only subjected to mild stimulation, while at other times both are the seat of acute inflamma- tion. The inflammation of the bowel produces a condition of collapse, which is seen also in various intestinal diseases, such as cholera. Sometimes the poisons (and also cholera) produce no very marked symptoms of gastro-intestinal disorder, but rather those of collapse, but there is no reason to believe that the collapse is due to any direct action on the central nervous system. In the frog, colchicine has little or no effect, but if the solution be exposed for some time to the air, it causes a prolongation of the muscular contraction similar to that seen after veratrine, and eventually a tetanus resembling that due to strychnine. Jacobj therefore believes that in mammals the effects are not produced by colchicine itself, but by a substance formed by its oxida- tion in the tissues, oxydicolchicine. The frog's tissues are unable to oxidize colchicine, but if oxydicolchicine be formed by the exposure of colchicine to the air, it produces these symptoms. Oxydicolchicine causes the same symptoms in mammals as colchicine. PREPARATIONS. Colchici Cormus (U. S. P., B. P.), the corm or bulb of Colchicum autumnale, 0.1-0.3G. (2-5 grs.). Extractum Colchici Cormi (U. S. P.), 0.03-0.1 G. (J-2 grs.). Extractum Colchici (B. P.), -1 gr. VINUM COLCHICI (B. P.) (10-30 mins.). Colchici Semen (U. S. P.), Colchici Semina (B. P.), the seed of Colchicum autumnale. Fluidextractum Colchici Seminis (U. S. P.), 0.1-0.3 c.c. (2-5 mins.). Tinctura Colchici Seminis (U. S. P.), 0.3-1 c.c. (5-15 mins.). Tincfura Colchici Seminum (B. P.), 0.3-1 c.c. (5-15 mins.). Vinum Colchici Seminis (U. S. P.), 2-5 c.c. 346 ORGANIC DRUGS ACTING AFTER ABSORPTION. The Vinum Colchici Radicis is the preparation usually prescribed. Colchicina (U. S. P.) (C 22 H 25 NO 6 ), an alkaloid obtained from colchicum, pale yellow in color, with a bitter taste and characteristic odor ; soluble in 22 parts of water and in alcohol. Dose, 0.5 mg. ( T n gr.). Therapeutic Uses. Colchicum has long been used in gout on purely empirical grounds. In fact, the pathology of gout is so obscure that no rational treatment for it can be looked for at the present day, and the efficacy of colchicum in this disease can, therefore, be argued solely from clinical experience, which here gives only uncertain indications. Up to a few years ago the routine treatment was wine of colchicum, but of late many physicians have denied that any benefit whatso- ever was obtained from its use. Others maintain that colchicum is at any rate the most efficacious drug available in many cases, and here the matter stands, but the use of colchicum in gout is not universal now, as it was formerly. Some attempt has been made to place the practice on a rational basis by showing that it increased the excretion of uric acid. But a number of other intestinal irritants have the same effect, and it now seems to be proved that gout is not due to a deficient excretion of uric acid, so that its increased elimination would not ex- plain the alleged beneficial effects of colchicum. Besides this increase in the uric acid excretion is by no means a constant result of colchicum medication, for it not infrequently has the opposite effect. And in gout the uric acid excretion does not seem to be modified at all by col- chicum. Colchicum has also been used in chronic rheumatism but here it is of little or no benefit. BIBLIOGRAPHY. Jacobj. Arch. f. exp. Path. u. Pharm., xxvii., p. 119. N. Paton. Brit. Med. Journ., 1886, i., p. 377, and Journ. of Anat. u. Phys. , xx., p. 267. Fawcett. Guy's Hospital Reports, lii., p. 115. XX. SAPONIN, SAPOTOXIN AND SOLANINE. Under this group are arranged a number of glucosides which have many features in common both in their chemical properties and in their pharmacological action. Many of them have not yet been completely isolated, and it seems not unlikely that several which are now believed to be distinct, will prove to be identical. Robert has found that many of them may be arranged in a chemical series C n H 2n _ 8 O 10 . Some have an acid reaction and form salts with the alkalies, while all possess the characteristic glucosidal reaction, being decomposed by acids and fer- ments into sugars and unknown inactive substances. The most poi- sonous among them are designated by the general term of Sapotoxins, while Saponin may be used to include the less active ones and certain innocuous isomers of the sapotoxins which are formed from them by boiling with alkalies. These terms as well as the popular names of several of the plants from which the active principles are derived, SAPOXIN, SAPOTOX1N AND SOLANINE. 347 refer to the property they possess of forming frothy, soap-like solutions in water and of holding insoluble bodies in suspension in it. Very often several of these bodies are found in a single plant, either several powerfully poisonous ones (sapotoxins), a mixture of sapotoxins and saponins, or saponins only. Saponins or sapotoxins are found in about 150 species of plants. The chief of these are : Quillaja saponaria, or soapbark (containing quillaja-sapotoxm and quillajac acid). Saponaria officinalis, or soapwort (saporubrin and saponiri). Cyclamen Europeum, or sowbread (cyclamiri). Poly gala senega (senegin and polygoMc acid). Agrostemma githago, or corncockle (agrostemma-sapotoxin). Gypsophila struthium and other species (gypsophila-sapotoxin). Chamaelirium luteum, or blazing star (chamcelirium-sapotoxin). Smilax, various species, including those known as sarsaparilla (sarsa- ponin, sarsapanlla-saponin and parillin or smilacin). In addition to the plants, which owe their action to ' the presence of these bodies, a number of drugs contain saponins along with other more important principles. Thus, an almost inactive saponin (digi- tonin) is met with in digitalis, and similar saponins probably occur in several others of the digitalis series although they have not yet been isolated. The most poisonous of these are the sapotoxins of quillaja, agros- temma and gypsophila, quillajac acid, and cyclarnin. Senegin is only about one tenth as poisonous as quillaja-sapotoxin, and the saponins prepared from the sapotoxins are still less dangerous. Another body closely resembling the saponins in action is Solanine, a glucosidal alkaloid found in many species of Solanum, such as S. nigrum (black nightshade), S. dulcamara (bittersweet), S. tuberosum (potato), and probably in some species of Scopolia. In Solanum nigrum and S. dulcamara it is accompanied by small quantities of one or more bases resembling atropine, while in dulcamara a glucosidal body, Dul- camarin, has been found also belonging to the sapotoxin series. Solanine is said to be generally accompanied by Solaneine, a nearly related alkaloid. Solanine breaks up on being heated with acids into sugar and a base, Solanidine, which retains the poisonous action. In some plants both solanine and solanidine seem to be present. Its chief importance arises from its occurrence in the potato, which has given rise to widespread poisoning in several instances. The amount of solanine in the potato is in general too small to provoke poisonous symptoms, even when enormous quantities are eaten, but when the potatoes begin to sprout in damp cellars, the percentage of solanine rapidly increases, especially in the green buds and the small young tubers. In old, rotting potatoes it may also become dangerously high, but cases of poisoning are more likely to arise from the use of the green, unripe potatoes than from those which are obviously unfit for use. Weil states that the increase in solanine seen in potatoes that 348 ORGANIC DRUGS ACTING AFTER ABSORPTION. have been kept too long is due to the presence of bacteria which form this alkaloid from the potato. In any case the potato skins contain nearly half of the solanine, and if these be removed before boiling, a considerable part of the alkaloid contained in the edible part is extracted by the water. Action. The sapotoxins possess a very irritant, local action, and produce acute inflammation of the alimentary canal and extravasa- tions in various organs, when they are carried to them by the blood. They also destroy the red blood cells when brought into contact with them. They have a harsh, acrid, unpleasant taste, and when swallowed pro- voke nausea and often vomiting, with pain and colic, and less frequently diarrhoaa. They are not absorbed by the normal epithelium of the alimentary canal, and therefore fail to produce general symptoms, un- less some lesion, such as gastric ulcer, is present. Thus pigs feed with avidity on Cyclamen and are unharmed by it unless some lesion of the intestine is present. The unbroken skin is not affected by a single application as a general rule, and absorption is extremely slow from the subcutaneous tissues, in which they act as irritants, however, and produce inflammation and suppuration. The sapotoxin derived from Agrostemma differs from the others in being absorbed fairly rapidly from the alimentary canal and from the subcutaneous tissues, so that more dangerous symptoms may arise from it than from the other members of the series. In an epidemic of solanine poisoning from potatoes described by Schmiedeberg, the symptoms consisted of headache, colic, vomiting and diarrhoea, general depression and weakness, and some mental con- fusion. In severe cases pallor or cyanosis, dilated pupils, short periods of unconsciousness with acceleration and then slowing of the pulse were observed. All the patients recovered in the course of ten days. In many cases some rise of temperature was noted. In experiments on animals, Perles found almost the same symptoms and the same post-mortem appearances as after sapotoxin. Diarrhoea was not so easily induced by solanine as by the poisonous potato, perhaps because the pure poison was absorbed from the stomach, while it was carried into the bowel when mixed with the other constituents of the potato. Solanine, on the other hand, seems more liable to cause nephritis than most sapotoxins, and albumin and haemoglobin are generally found in the urine. When solanine is administered by the mouth, most of it is decomposed in the tissues, for very little reappears in the stools and urine as solanine and solanidine. When these bodies are injected directly into the blood vessels, they induce much more characteristic changes, which very often prove fatal after a longer or shorter interval. Very large quantities thus injected may kill animals within a few minutes from respiratory paralysis, and no characteristic appearances are to be found post mortem. Smaller doses induce depression, loss of appetite, sometimes vomiting and diar- rhoea, general weakness and collapse, with some dyspnoea and irregular, SAPONIN, SAPOTOXIN AND SOLANINE. 349 feeble pulse. Weak convulsions appear just before the failure of the respiration, while the heart continues to contract for some minutes longer. In these cases ecchymoses are found in the serous membranes, pericardium, pleura and peritoneum, and occasionally in the kidneys. Endocarditis has been observed in some instances, but the most impor- tant alterations occur in the stomach and intestines, the mucous mem- brane of which is swollen and congested and contains numerous blood extravasations. The lymphatic glands of the abdominal cavity are also swollen and congested and often filled with haemorrhages. Oc- casionally the kidneys are found to contain numerous blood casts fill- ing the lumen of the tubules, and in these cases albumin and hemo- globin appear in the urine before death. In Cyclamen poisoning (from intravenous injection) haemoglobinuria is one of the earliest symptoms. The saponin bodies are general protoplasmic poisons, destroying life wherever they come in contact with living tissues in sufficient concentra- tion. Their irritant action on the mouth, throat, and stomach is the cause of the nausea and vomiting observed when they are administered in this way, and they cause sneezing and coughing from the same action in the nose and throat. On other mucous membranes, such as the con- junctiva, and in wounds, they cause similar irritation and inflamma- tion, which may be followed by suppuration. A form of local anaes- thesia often follows this irritation, the terminations of the sensory nerves apparently being benumbed, but the preliminary irritation pre- cludes their use for this purpose. Even the unbroken skin may be irritated when they are applied re- peatedly or rubbed on in the form of ointment. This irritation is be- trayed by redness, heat, itching, and eventually by the formation of pustules. Their local effects when injected subcutaneously also indi- cate their irritant properties. When the individual organs are exposed to the action of saponin bodies by the direct application of solutions to them, a similar poison- ous action is elicited. Muscle contracts more weakly even in dilute solutions, is eventually entirely paralyzed, and is altered in structure, the transverse striae of voluntary muscle and of the heart becoming very indistinct. Nerves exposed to solutions are also paralyzed in the same way, and the movements of cilia cease at once when they are ex- posed to sapotoxin bodies. The blood undergoes characteristic changes when it is acted on by saponin either in the vessels or in the test-tube. The coagulation is said to be accelerated by small quantities of cycla- min, and is certainly retarded by larger, but the most striking effect is the destruction of the red corpuscles and the liberation of the haem- oglobin, which forms " laky " blood. Even one part of cyclamin added to 100,000 parts of diluted blood completely destroys the red blood cells, while haemoglobin appears in the serum when consider- ably less poison is added. The other saponin bodies act less power- fully in this direction than cyclamin, but still produce distinct solution 350 ORGANIC DRUGS ACTING AFTER ABSORPTION. of the substance of the red corpuscles. When a saponin is injected into the blood of a living animal this destruction of the red blood- cells takes place to some extent, and the plasma contains haemoglobin, while the blood corpuscles are considerably diminished in number. This haemolytic action is not the result of changes in the haemo- globin, for the corpuscles are found to be more permeable by salts also, and this even under conditions which prevent the liberation of haemoglobin (Stewart) ; it has recently been shown that saponin acts more powerfully on the red blood-corpuscles in the absence of serum, and that the stromata of the corpuscles are the parts affected and not the haemoglobin ; finally, it appears extremely probable that the haemol- ysis is due to the affinity of saponin for the cholesterin and other lipoids of the corpuscles, the changes in the physical condition of the cholesterin through the permeation of the glucoside resulting in the rupture of the cell and the liberation of the haemoglobin. The serum retards the action of saponin on the corpuscles by fixing some of it in combination with its lipoid constituents (Ransom, Hedon). The circulation in mammals is comparatively little aifected until just before death, when the blood-pressure falls rapidly and the pulse becomes weak and slow. The heart continues to beat for a short time after the respiration ceases, but is very weak, and finally stops, even although artificial respiration is maintained. The isolated frog's heart is paralyzed by sapotoxins in the same way as the isolated muscle. In many experiments, death would seem to be caused by collapse fol- lowing the changes in the alimentary canal. In others, however, when only small quantities of the poison have been injected, no such changes are observed, but the animal dies after a few days, presenting no dis- tinct symptoms except general weakness and depression. On the other hand, very large quantities injected into a vein may prove fatal within a few minutes, and here again no symptoms of intestinal action may appear. It is therefore believed that in addition to their irritant effects these bodies have a special action on the central nervous system, although it is impossible at present to specify its nature. The respira- tion is in all cases the first vital function to be suspended. Sapotoxin applied directly to the spinal cord in the frog first provokes convulsive twitching and clonic spasms and then paralyzes the animal, but it may be questioned whether it would have the same effect when carried in the blood. The sapotoxins are poisonous to invertebrates apparently, unless they are protected by a shell, through which they can not penetrate. Thus the amoeba and other simple organisms cease their movements, while intestinal worms are first excited and then paralyzed in the presence of some of the group. SAPONIN, SAPOTOXIN AND SOLANINE. 351 PREPARATIONS. ftuillaja (U. S. P.), ftuillaiae Cortex (B. P.), Panama bark, Soap bark, the inner bark of Quillaja saponaria. Fluidextractum Quillajce (U. S. P.), 0.2 c.c. (3 mins.). Tinctura Quillajce (U.S. P.), Tinctura Quillaice (B. P.), 2-4 c.c. (30-60 mins.). Sarsaparilla (U. S. P.), the root of Smilax ofiicmalis, S. medica, S. papy- racea and of other species of Smilax. Fluidextractum Sarsaparilla? (U. S. P.), 4 c.c. (1 fl. dr.). Fluidextractum Sarsaparillce Compositum contains sassafras, liquorice, and meze- reum. 4 c.c. (1 fl. dr.). Syrupus Sarsaparitlce Compositus (U. S. P.) contains liquorice, senna, and the oils of sassafras, anise and wintergreen. 10-15 c.c. (2-4 fl. drs. ). Sarsae Radix (B. P.), sarsaparilla, the dried root of Smilax ornata, im- ported from Costa Eica and known as Jamaica sarsaparilla. Liquor Sarsoe Compositus Concentratus (B. P.) is formed from sarsaparilla, sas- safras root, guaiacum wood, liquorice and mezereum. 2-8 fl. drs. Extractum Sarsa? Liquidum (B. P.), 2-4 fl. drs. Senega (U. S. P.), Senegse Radix (B. P.), the root of Polygala Senega. Fluidextractum Senega? (U. S. P.), 0.5-1 c.c. (10-15 mins.). Syrupus Senega (U. S. P.), 4-8 c.c. (1-2 fl. drs.). Tinctura Senegce (B. P.), -1 fl. dr. Liquor Senegas Concentratus (B. P.), ^-1 fl. dr. Infusum Senega? (B. P.), ^-1 fl. oz. ; as a draught, 2 fl. oz. Hemidesmi Radix (B. P.), the dried root of Hemidesmus Indicus. Syrupus Hemidesmi (B. P.), J-l fl. dr. Therapeutic Uses. The drugs of this group are all quite superfluous. They may be used to increase the bronchial secretion in cough through the nausea caused by their slight irritant action in the stomach, but they have no advantages over such drugs as ipecacuanha or apomorphine ; the syrup of senega is often prescribed in expectorant mixtures for this purpose. Sarsaparilla has been supposed to have an obscure action on the nutrition, and has some reputation in the treatment of syphilis, but there is no reason to believe that it is of any service here or in any other condition, although it may be used as a vehicle for the administration of mercury and iodide of potassium. For this purpose the compound syrup U. S. P. or compound liquor B. P. is the best preparation. Quillaja has been used to some extent as an expectorant, more largely to form emulsions and to suspend insoluble powders. Its poisonous action ought, however, to preclude its use for this purpose. It is frequently stated that members of the sapotoxin series are anti- dotes in digitalis poisoning ; but this is founded on experiments in which both drugs were applied directly to the frog's heart, and there is no rea- son to suppose that they would oppose each other in man, especially if given by the mouth, as sapotoxin is absorbed only with great difficulty. Dulcamara has been used to a limited extent as a sedative and hyp- notic and also as a diuretic and diaphoretic and in some skin diseases. It does not seem to possess any properties which would render it of value in medicine, and might well be dispensed with. Another series of bodies resembling the saponin series in their effects are known as Solvines, Oleites, Polysolve, etc., and are derived from oleic and other similar acids by the action of sulphuric acid. The best known is that formed from ricinoleic acid. According to Kiwull, solvines have the same 352 ORGANIC DRUGS ACTING AFTER ABSORPTION. destructive action as sapotoxin. They have been used in medicine to form emulsions, but their use here is to be deprecated on the same grounds as that of quillaja. BIBLIOGRAPHY. Robert. Arch. f. exp. Path. u. Pharm., xxiii., p. 233. Stewart. Journ. of Exp. Med., vi., p. 257 ; Journ. Med. Research, viii., p. 268. Hedon. Arch, internat. de Pharmacodyn., viii., p. 381 ; ix., p. 393. Rartsom. Deutsch. med. Woch., 1901, p. 194. Pachorukow, Atlass u. Tufanow. Arbeiten a. d. Pharm. Inst. zu Dorpat, i. Kruskal. Ibid., vi., p. 1. Kiwull Ibid., iii., p. 1. (Solvin.) SchuLz. Ibid., xiv., p. 1. Bruere. Journ. of Med. Research, viii., p. 362. Solanine. Husemann u. Balmanya. Arch. f. exp. Path. u. Pharm., iv., p. 309. Perks. Ibid., xxvi., p. 88. Meyer u. Schmiedeberg. Ibid., xxxvi., p. 361. P/uhL Deutsch. med. Woch., 1899, p. 753. Weil. Arch. f. Hygiene, xxxviii., p. 330. XXI. ASPIDOSPERMA, OR QUEBRACHO. The bark of Quebracho bianco (Aspidosperma quebracho) contains a num- ber of alkalojds which are probably very similar in chemical composition and which seem to possess almost the same action. They are Aspidospermine, Aspidospermatine, Aspidosamine, Hypoquebrachine, Quebrachine and Quebracha- mine. Another species of Aspidosperma, Payta, contains two alkaloids, Pay- tine and Paytanine, of which Paytine resembles closely the Quebracho alka- loids in its pharmacological action. These alkaloids all produce nausea but even after large doses vomiting does not occur except after Aspidosamine. The nausea is accompanied by the usual concomitant symptoms salivation, increased secretion of mucus in the respiratory tract, depression and alternately rapid and slow pulse. Large quantities often cause symptoms of central nervous stimulation, tonic contractions and convulsions. The respiration is quicker and deeper after small quantities, but after lethal doses becomes slow and weak, and finally ceases. Periodic respiration often occurs before the final standstill, a series of deep dyspnoeic movements alternating with several shallow, insufficient ones. The failure of the respiration is the cause of death in mammals, the heart continuing to^ contract for some time longer. After Aspidosamine, there is no stage of quick and deep respirations, but the breathing is rendered slow at once and soon becomes periodic. These symptoms are generally ascribed to a direct action on the central nervous system, which is first stimulated and then depressed. The chief seat of action seems to be the medullary centres and the spinal cord, although the basal ganglia may also be more or less involved. The stimulation of the medullary centres explains the nausea and vomiting and also the changes in the respiration, while the convulsions and increased reflex excitability point to the spinal cord. The terminations of the motor nerves in voluntary muscles are paralyzed by aspidosamine and quebrachine in the frog, not by the other alkaloids ; but all of them lessen the strength of muscular tissue and eventually paralyze it in these animals. Neither of these results has been observed to follow the injection of the alkaloids in mammals. The circulation in mammals is atiected indirectly through the nausea, and the heart may be slowed by very large doses. Wood states that even moderate quantities reduce the blood-pressure in the dog. Eloy and Huchard observed diarrhoea and an increased secretion of urine occasionally follow the administration of the alkaloids, and they also describe QUININE. 353 a curious coloration of the blood which they ascribe to a diminution of the haemoglobin. Penzoldt attributed the asphyxia to changes in the red cells, but the subject of the action of these alkaloids on the blood requires further investigation. None of the quebracho alkaloids is very poisonous, but of the series que- brachine is the most toxic, and aspidosamine and aspidospermatine follow it closely. Aspidospermine, quebrachamine and hypoquebrachamine are com- paratively weak. Commercial ' ' aspidospermine " is a mixture of all the alkaloids along with other bodies. It is sometimes prescribed in doses of 1-2 mgs. (fa-yv gr.). Aspidosperma was advised by Penzoldt in the treatment of dyspnoea from a variety of causes, and his statements have received a certain amount of support from clinicians. The special conditions in which it has been advised are dyspnoea from pulmonary disease, especially emphysema, and from car- diac weakness and asthma. Its action on the respiratory centre may ex- plain to some extent the benefits derived from it, but the increased secretion of the bronchi produced by the nausea may also be of some importance. It has also been employed as an antipyretic, and has been shown by Eloy and Huchard to lower the temperature in animals. BIBLIOGRAPHY. Harnacku. Hoffman. Zeitschr. f. klin. Med., viii., p. 471. Eloy u. Huchard. Arch, de Phys. [3], vii., 1886, p. 236. Gutmann. Arch. f. exp. Path. u. Pharm., xiv., p. 451. Wood. Univ. of Pennsylvania Med. Bull., Sept., 1903. XXII. QUININE. The barks of various species of Cinchona and Remijia (Cuprea) con- tain numerous alkaloids which seem to resemble each other closely in their chemical and pharmacological properties. The best known of these are Quinine, Quinidim, or Conquinine, Cinchonijie and Cinchoni- dine; the others, amounting to some twenty in number, are believed to resemble these in their effects on the organism, but very little has been done to determine this, and nothing is known regarding their relative activity. The cinchona alkaloids are derivatives of quinoline. Cinchonine and cinchonidine are isomeric (C 19 H 22 1S" 2 O) and perhaps contain two quinoline molecules, while quinine and quinidine (C 20 H 94 N 2 O 2 ) are methoxyl compounds of cinchonine. 1 Cinchona bark contains besides these alkaloids several acids, includ- ing tannins, and some neutral substances. The cinchonas are natives of Western South America, but are now cultivated in India and Java. It seems questionable whether the vir- tues of the bark were known by the native Indians before the invasion of the Spanish, and its introduction into medicine dates from about 1630-1640 ; its name bears testimony to its efficacy in the case of the Countess of Chinchon in 1638. 1 The other alkaloids of this series which have been identified are homocinchonidine, conquinamine, quinamine, cusconine, concusconine, aricine, cusconidine, cuscamine, cuscamidine, hydroquinine, hydroquinidine, hydrocinchonine, cinchonamine, quaira- mine, conquairamine, quairamidine and conquairamidine, while several others are said to have been separated by some authorities, but are rejected by others. The acids generally acknowledged to be present in cinchona are quinic, quinovic, quinotannic, quinovatannic, caffeotannic and oxalic, while the neutral bitter substances have been named quinovin, quinova-red and cinchona-red. 23 354 ORGANIC DRUGS ACTING AFTER ABSORPTION. Action. Quinine differs from most of the other important alkaloids in acting not on some specialized form of living matter, but on the gen- eral nutrition of almost all forms of protoplasm. Other alkaloids, such as strychnine, are also possessed of similar effects as regards nutrition, but their strong affinity for, and intense action on some special tissue, prevent their effects on the fundamental (properties of living matter from being elicited in the higher animals. Quinine is therefore often termed a protoplasm poison because its action extends with but little variation throughout most forms of living matter ; on the other hand the marked effect of strychnine on the nerve cell causes it to be classed among nerve poisons, although in organisms devoid of a nervous sys- tem it resembles quinine in its effects. The effects of quinine on pro- toplasm generally consist in transitory augmentation of its activity, followed by depression and death. The action of quinine on Undifferentiated Protoplasm, such as is found in the unicellular organisms and in the ovum, is therefore of greater interest than that of most alkaloids. Binz found that while very minute quantities sometimes increase the movements of the amoaba and infusoria at first, large amounts paralyze them immediately, and the protoplasm assumes a darker granular appearance. The rhythmic movements of ciliated organisms are rendered slow and finally arrested by very dilute solutions. The microbes of putrefaction are also acted upon by quinine, although they seem more resistant than the protozoa ; still, quinine solutions have considerable antiseptic power, equalling that of carbolic acid, according to some observers. The alcoholic, lactic and butyric fermentations are retarded, or entirely prevented by quinine through its effects on the organisms, but it is apparently devoid of action on some of the lower forms, for moulds (Penicillium) grow freely in solutions of the salts ; so that the alkaloid seems to have a selective action here, such as is observed also in its effects on the ferments of the higher animals. Another example of its action on the vegetable cell is that discovered by Darwin in some insectivorous plants (Drosera), in which the movements seem to be first excited and later paralyzed by the quinine salts. The influence of quinine on the reproductive cells of animals has been carefully studied by O. and R. Hertwig, who found that both the spermatozoon and the ovum of the sea-urchin are injured by the addi- tion of quinine to the sea-water, the movements of the former being paralyzed, and the stages preceding impregnation in the latter progress- ing more slowly, or actually retroceding. When quinine is applied after the male nucleus has entered the ovum, the complete conjugation is delayed and the whole process is rendered abnormal by the admis- sion of several spermatozoa. Quinine applied still later prevents or delays the division of the ovum through its effects both on the nucleus and on the general protoplasm of the cell. The individual cells of more complex organisms are affected in the same way as these more simple ones. This was first demonstrated in QUININE. 355 the leucocytes by Binz, and after some opposition has been generally accepted. When a drop of blood is examined under the microscope, the white cells are observed undergoing constant changes of form and position exactly similar to those of the amreba, but minute quantities of a quinine salt are sufficient to stop all movements at once, and the leucocytes assume a spherical form, become darker in color and gran- ular, and soon break up into debris. In the blood vessels similar changes occur when quinine is applied locally, as to the frog's mesen- tery ; the leucocytes again become darkly granular, and ceasing their creeping movements, are carried along by the current much more rap- idly than usual. They are no longer observed to push their way through the vessel walls, and if they have already penetrated into the tissues their movements are arrested. If irritation be applied to the part, no such accumulation of leucocytes occurs in the tissues as in the unpoi- soned animal, and if an irritant has been applied first and the leuco- cytes have poured out of the vessels before the quinine is applied, the process is arrested at once on its application. This effect was explained by Binz as due to the poison acting on the leucocytes, and although attempts have been made to explain it by some change produced on the vessel wall by the drug, there now seems no reason to question the correctness of his view. Similar results are observed when the drug is not applied locally, but carried to the part by the vessels ; the move- ments of the leucocytes in the vessels are less distinct ; they are carried along passively in the general current, assume a spherical form, and have much less tendency to escape into the general tissues, and at the same time the number of the leucocytes in the blood undergoes a con- siderable diminution. It would be unjustifiable to infer from these experiments that the therapeutic dose of quinine inhibits the move- ments of the white blood cells in the human body, and it is no part of Binz's theory that this occurs. The effect of quinine on the leucocytes is merely an example of its effects on the tissues generally. At the same time, the number of leucocytes in the human blood is diminished by ordinary quantities of quinine, showing that the action on the frog's leucocytes extends also to those of man, even when the quinine is ab- sorbed from the stomach and intestine. Other evidence of the action of quinine is gained from processes which may be regarded as due to Unorganized Ferments. Thus the oxidizing action of drawn blood was shown to be dimin- ished in several experiments performed by Binz. Immediately after its issue from the vessels the unpoisoned blood undergoes a diminution of its alkalinity, from the oxidation of some unknown substances at the expense of the oxyhsemoglobin, which is partially reduced. This acid fermentation is prevented by the addition of quinine to the blood. Even when pieces of tissues are added and the reduction of the arterial blood would ordinarily be much accelerated, quinine prevents or retards the change. A similar inhibition of the oxidizing action of the blood is shown by its failure to form the blue oxidation product of guaiac, 356 ORGANIC DRUG 'S ACTING AFTER ABSORPTION. or to decolorize indigo when it is applied to it along with quinine. 1 Or instead of blood a slice of potato or a watery extract of a liv- ing plant may be used. From these experiments the inference is drawn that quinine hinders the action of the oxidizing ferment of the blood and tissues. On the other hand, Jacquet found that it had little or no effect on the oxidation of substances passed through the vessels of excised organs. Another ferment action which is said to be retarded by the presence of quinine is the coagulation of the blood. The gastric and pancreatic ferments are also said to be rendered less active by the addition of quinine in artificial digestion experiments (Rossbach), while the ptyalin of the saliva, emulsin and diastase are unaffected (Binz). These experiments indicate that quinine hinders some, if not all, of the processes which normally occur in living matter, and which are expressed in movement and in various chemical products ; they indi- cate in addition that this action is not confined to the intact protoplasm, but extends to some of the ferments. When very minute quantities of the drug are applied, the stage of depression is sometimes preceded by one of augmented activity. Rossbach found that quinine and several other alkaloids exercise some influence on solutions of the proteids, which coagulate at a lower temperature than usual, but it is impossible to determine at present whether this fact is connected with their effects on living tissue or is merely a coincidence. Among the Vertebrates, also, small quantities of quinine give rise to disturbances of the nutrition, but before discussing these, it may be well to indicate the symptoms induced by poisonous doses. In the frog, a short stage of increased reflex excitability is followed by the loss of spontaneous movements, the arrest of respiration and paralysis of the spinal cord. In mammals, the spinal cord is said to be stimulated by small quantities and then to be depressed. The respiration is sometimes accelerated in the beginning, but is afterwards weakened, and its failure is the cause of death. General depression and muscular weakness are usually the only cerebral effects noted, and the tremor and convulsions said to occur in some instances may be due to the use of impure quinine. The heart is often accelerated at first, but is afterwards slow and weak, while the blood- pressure, after a slight increase, declines progressively. According to ISan- tesson, quinine given by the stomach has comparatively little effect on the heart and blood-pressure in mammals. These symptoms point to a prelimi- nary stage of stimulation, followed by depression of the Central Nervous System and heart in the vertebrates, corresponding to the two stages ob- served in the simpler organisms. They are only elicited by very large quantities of the drug and have perhaps received greater attention than they merit at the hands of experimental pharmacologists. The depression of the reflexes of the frog was at one time attributed to a stimulation of the in- hibitory centres of Setschenow, and this was supported by the fact that it could be removed at first by division of the medulla oblongata. It seems 1 The well-known guaiac experiment is performed as follows : A fresh solution ol guaiac resin in alcohol, to which some peroxide of hydrogen has been added, it divided into two parts. To the one a minute quantity of quinine is added, and one 01 two drops of blood are then allowed to flow into each part. The one containing the quinine remains uncolored, while the other assumes a blue tint from the oxidation oi the guaiac by the unpoisoned blood. QUININE. 357 more probable, however, that the local irritation of the acid salts usually injected caused the temporary depression indirectly, and that the action on the central nervous system consists in a transient stimulation followed by lasting depression. The statement that the depression is due to the weak- ness of the heart seems incorrect. The changes in the Circulation in mammals are caused by a preliminary contraction of the arterioles and acceleration of the heart, followed by dila- tion of the former and slowing and weakening of the latter. In both cases the action is probably a direct one on the muscle of the arterioles and heart, although some investigators consider the acceleration due to depression of the inhibitory mechanism in the heart or in the medulla oblongata. The effects of quinine on the isolated frog's heart have been studied carefully by Santesson, who found that the action was entirely muscular and consisted in slowing, accompanied by marked decrease in the strength of the contrac- tions. In fatal poisoning in mammals the heart is generally very much weakened when the respiration ceases, but continues to beat for some time afterwards. Quinine acts upon Muscle in the same way as upon the simple organisms, temporarily increasing its power and subsequently weakening it. Thus Santesson found that the strength of the individual contractions was in- creased, and that a contraction occurred against greater resistance than normally, but when the stimulation was repeated, fatigue set in sooner than in the unpoisoned muscle. Large quantities of quinine throw the muscle into rigor, which resembles that produced by caffeine, and is probably asso- ciated with its action in accelerating the coagulation of myosin (Fiirth). The Nerve Trunks are said to be remarkably tolerant to solutions of qui- nine, which do not lessen their irritability when applied locally in sufficient quantity to cause marked abnormalities in the muscular contraction. No sufficient evidence has been brought forward that quinine affects the periph- eral ends of the motor or sensory nerves. The number of Leucocytes in the blood is much diminished by the administration of quinine in man and the lower mammals, but it is unknown how this is effected. The statement that the normal Spleen undergoes a contraction in size and partial atrophy after quinine, while not improbable in itself, is not supported by experiments in which accurate methods were used. A slight increase in the amount of Urine excreted has been observed some- times, but does not seem constant. It is attributed to the action of the qui- nine on the renal epithelium, by which it is excreted. The other secretions do not seem to be altered by quinine unless it is applied directly to the cells in large quantity by injecting solutions into the duct of the gland. The statement is made that the glycogenic function of the liver is altered so that less sugar than usual is supplied to the blood, and there is some evidence that other hepatic functions are less active than usual. Cinchona preparations and quinine have the same action on the appe- tite and digestion in man as the simple bitters and nux vomica. Or- dinary therapeutic doses often produce no very obvious symptoms, the most frequently observed effect consisting in derangement of the Sense of Hearing, less frequently of that of Sight. Ringing or roaring sounds in the ears, accompanied by slight deafness, are produced by moderate quantities and large doses are not infrequently followed by complete loss of hearing for a time. Contraction of the field of vision is ob- served less often, but in some cases total blindness has been produced and has lasted for several days or even weeks. Color-vision is es- pecially liable to be rendered imperfect or temporarily paralyzed by quinine ; these disorders of sight are accompanied by a very marked 358 ORGANIC DRUGS ACTING AFTER ABSORPTION. contraction and even obliteration of the retinal vessels and sometimes by degenerative changes in the retinal nerve-cells and even by atrophy of the optic nerve. It is still undecided whether the vascular changes or the nervous degeneration is the primary lesion, but the majority of investigators at present favor the view that the constriction of the ves- sels is merely an accompaniment of the graver effects on the ganglionic structures. The symptoms in the ear have generally been regarded as the result of congestion and haemorrhages in the tympanum and laby- rinth, but Wittmaack has recently shown that this view is founded on erroneous observations, and states that degenerative changes occur in the spiral ganglion in the cochlea exactly analogous to those described in the retina. Quinine possesses some irritant action which betrays itself in discomfort in the stomach and eructation after large and re- peated doses by the mouth, and by pain and tenderness when it is injected subcutaneously ; but this drawback is not of so much import- ance as in the case of many other drugs. Large doses of quinine produce some confusion and depression with a sense of fulness and heaviness in the head from their action on the Cerebrum, and this is sometimes accompanied by uncertain gait and slow pulse. Very few cases of fatal poisoning have been satisfactorily determined to be due to quinine, although a considerably larger num- ber have been attributed to it. In these cases marked weakness of the heart and collapse accompanied by loss of sight and hearing, muscular weakness, apathy, slow, gasping respiration and finally unconscious- ness and total failure of the respiration were observed. In some cases delirium and convulsions have been noted, but it may be doubted whether the preparation did not contain other members of the cin- chona alkaloids. Enormous doses of quinine sulphate have been swallowed without any serious results. Thus in one case thirty grammes (one ounce) produced only some confusion and noises in the ears. Probably only a small quantity of the drug was absorbed, as the sulphate, which is generally used, is exceedingly insoluble. The extensive use of quinine in therapeutics has demonstrated that many persons have curious Idiosyncrasies in regard to it. This is be- trayed in many cases by the development of ear symptoms after com- paratively small doses, but in others symptoms arise which do not appear in the great majority of people even after large doses. The commonest of these are skin eruptions, of which a large variety have been described, and which can be distinguished from ordinary diseases of the skin only by the history or by the detection of quinine in the urine and other excretions. These exanthemata are often accompanied by some rise in temperature, which has received more attention than it appears to deserve, for it is rare and even when present is of insig- nificant extent. Other less important effects, which have been occa- sionally noted, are gastric discomfort and diarrhoea. In very rare cases the administration of quinine is followed by fever and hsemoglobinuria (black water) or albuminuria ; the patients are in almost every case QUININE. 359 sufferers from old malarial infection, but there is no question that in many cases the symptoms arise only when quinine is given. The action of quinine on the Uterus is the subject of a large number of memoirs, but is still quite uncertain. Abortion certainly occurs occasionally after its use in malaria, while in other cases labor pains may be induced by quinine. Many physicians use it during labor if the pains cease or if they seem to be too weak to expel the child. But opinions differ as to its efficiency, for while some regard it as the most useful of remedies for this purpose, others have found it to fail in the great majority of cases and regard this action as an idiosyncrasy con- fined to a small proportion of individuals. It is quite impossible to state how quinine acts here, but is seems most likely that the uterine muscle is affected directly. In the Alimentary Tract, quinine and the cinchona preparations act in the same way as the simple bitters (page 56). Quinine delays proteolysis in experiments in artificial digestion. The constant effects of quinine on the Metabolism, which are pro- duced by quantities of the drug too small to have any further action except in specially susceptible individuals, are of much greater interest and importance than the symptoms already mentioned. This alteration of the tissue change occurs throughout the mammalia, and consists in a marked diminution in the destruction of the nitrogenous constituents of the tissues. After the administration of quinine, the nitrogen in the urine is found at first slightly augmented for a few hours, but then un- dergoes a diminution of considerable extent, due to a restricted produc- tion of all the nitrogenous constituents of the urine, but especially of the urea and uric acid. The phosphates and sulphates undergo a corre- sponding alteration, but all metabolic changes are not affected, for the carbonic acid exhaled and the oxygen absorbed by the lungs pre- sent no marked alteration in amount, so that the oxidation of the tissues cannot be said to be altered, but only the breaking down of the nitroge- nous bodies. This absence of effect on the oxidation of the body is not what might have been expected from the experiments of Binz and others on the simpler tissues, for these showed that oxidation of all kinds was retarded by quinine. On the other hand, it corresponds with Jac- quet's experiments on the oxidizing ferment of the tissues, and has been attested by too many observers to allow of any doubt as to its correct- ness. In the case of several other drugs the diminution of the urea is compensated for by the increase in the other nitrogenous bodies in the urine, but the fall in the total excretion of nitrogen after quinine points to an alteration of the metabolism of the body in general, and not to the paralysis or destruction of the organs which change the first products of the nitrogenous metabolism to the simpler forms in which they are finally excreted. The oxygen absorbed and the car- bonic acid excreted by the tissues are generally held to measure the amount of work done and heat formed by the muscular and other movements of the body, and quinine therefore does not seem to affect these functions, while it would appear that some other processes, per- 360 ORGANIC DRUGS ACTING AFTER ABSORPTION. haps the death, growth and repair of the tissues, are less active than normally. At any rate the nitrogenous food is not dissipated so rap- idly, but is stored up in the body in some unknown form, for v. Noorden found that under constant diet the nitrogen excretion diminished under quinine and this diminution continued for two days after the treat- ment was stopped. The nitrogen absorbed from the alimentary canal remained unchanged, and a certain amount of proteid food must there- fore have been added to the body and saved from the decomposition which it would have undergone in ordinary circumstances. The influence of quinine on the metabolism is closely connected with its effects on the body Temperature. It was early observed that besides its specific effects in malaria, quinine often depressed the tem- perature and improved the condition in a number of other fevers. This was long supposed to be due to some action that it exercised on the central nervous system, but when the nervous theory of fever fell into disrepute, this explanation also came to be looked upon with suspicion, and was finally disposed of by the experiments of Binz and others, who showed that quinine lowered the fever temperature after division of the spinal cord. Binz therefore attributed the antipyretic effects of quinine to its direct action on the tissues, and this explanation is gen- erally held to be correct. It is to be remarked that while there is no question as to the reduction of the temperature effected by quinine in many cases of fever, it has little effect upon the normal temperature. In some cases a slight fall in the thermometer is observed, but it is never very considerable, and often no results follow its administration, or a rise of 0.1 0.2 C. may occur. Gottlieb found that the fever temperature produced in rabbits by injury of the region of the corpus striatum was reduced by quinine, and that the regulation of the heat production according to the temperature of the surrounding air was not impaired by it. Thus, when the tem- perature of the cage was kept at about 30-32 C., and animals poisoned with morphine and some other drugs had fever temperature, the rab- bit to which quinine had been administered, showed little change from the normal. From this he infers that the heat-regulating mechanism of the brain is not affected by quinine, and that the reduction of tem- perature, when it occurs at all, is due to alteration in the metabolism. In a later research the same author found by calorimetric experiments that the warmth production was lessened by quinine, both in normal animals and in those in which fever had been induced by injury of the corpus striatum. This lessened production was accompanied in Gott- lieb's experiments by a fall in the output of heat, the regulating appa- ratus tending to counterbalance the reduced formation in the same way as in normal animals. In other experiments, however, quinine has been found to induce dilatation of the skin vessels and a corre- sponding increase in the heat loss. In other words, quinine appears to lessen the heat formation through its action on the tissues, and this is sometimes compensated for by a decrease in the heat loss, but in other instances the regulation fails and the temperature falls from the QUININE. 361 FIG. formation being lessened and the loss remaining unchanged or even being increased. This explanation of the antipyretic effects of quinine is not without difficulties, however. For the chief source of heat in the body is the oxidation of the carbohydrates, but in healthy animals quinine does not lessen the amount of carbonic acid excreted, as it might be ex- pected to do if it reduced the heat formation by restricting the com- bustion in the tissues. Some writers, therefore, hold that the fall in temperature is really the effect of dilatation of the skin vessels and increased heat loss. This explanation is not that generally accepted, however, and while it is not denied that the augmented output of heat may in some conditions contribute to the fall in temperature, the anti- pyretic action of quinine is still regarded as due for the most part to its retarding the metabolism ; it has been suggested that while the combustion in the normal tissues is not affected by quinine, the presence of fever poisons throws them into a state of aug- mented activity in which they are more susceptible to its sed- ative action, and that even in the normal organism a reduction of the temperature might be in- duced if sufficient of the drug other symptoms. Diagram to illustrate the relation of the warmth output and internal temperature (after one of Gott- lieb's experiments). The unbroken line represents the changes in the warmth output, which may be estimated by measuring its distance from the ab- scissa A B. The dotted line represents the internal temperature. From .4 to H, normal. At If an in- jury to the brain caused a marked diminution in the heat output and a corresponding rise in the in- ternal temperature. At Q quinine was administered and was followed by an immediate fall in the inter- nal temperature, while the heat output was practic- ally unchanged. Contrast Fig. 35. could be ingested without exciting In this connection it is of interest to remember that in fever the nitrogenous decomposition is much increased, while quinine has a directly opposite effect. The diminution in the nitrogenous metabolism may also lead to an increased resistance being offered by the tissues to the cause of the fever, or may lessen the poisonous pro- ducts circulating in the blood. In addition, the microbes of fever may themselves be rendered less active by the drug, although this antiseptic action would appear to be of subordinate importance, as many of the pathogenic forms have been found to offer great resistance to it. Quinine has much more effect in reducing temperature when it is administered in the beginning of a natural remission than when it is given during a rise of the thermometer. This property is shared by most antipyretics and will be treated of at greater length under the antipyrine series. 362 ORGANIC DRUGS ACTING AFTER ABSORPTION. Excretion. Quinine appears in the urine within a short time (30 minutes) after its exhibition by the mouth, and about one half of the quantity absorbed is excreted within six hours. After this it passes out of the body more slowly, and traces may be detected in the urine seventy-two hours after its administration. In some fevers the ex- cretion is said to be considerably retarded. Kerner found that some of the quinine absorbed was partially hydrated in the tissues and ex- creted as dihydroxyl-quinine, but if any such change occurs, it can affect only a very small proportion of the alkaloid, as over ninety per cent, of that ingested has been recovered unaltered from the urine. 1 Of the Other Cinchona Alkaloids,quinidme or conquinine resembles quinine most closely in its effects, which are somewhat weaker, however. Cincho- nine, while very similar to quinidine in most points, has some tendency to produce convulsions, but this effect is much more liable to occur under cin- chonidine which save for its resemblance in other features to quinine, would be entitled to be classed among the convulsive poisons. These convulsions are of an epileptiform character, and are only produced by very large doses, but Albertoni discovered that even small quantities administered to epilep- tics increased the number of the attacks. He found that these epileptiform seizures were not prevented by the removal of the cerebral cortex in dogs, and that the irritability of the motor areas was not altered by cinchonidine, and therefore concluded that the poison produced these symptoms by acting on some lower division of the central nervous axis. It is believed by many, however, that epileptic attacks can be elicited only when the cerebral cortex is intact, and although no results directly opposed to those of Albertoni have been recorded, the question must still be regarded as an open one. In other respects cinchonine and cinchonidine differ from quinine only in the degree and not in the kind of their action. Cinchonamine possesses an even more marked convulsant action than cinchonidine. The effects of the other alkaloids have not been the subject of much in- vestigation, but they seem to differ from quinine chiefly in their effects on the central nervous system. These are not entirely absent in quinine itself, for, as has been stated already, the reflex irritability is at first increased and then diminished in both frogs and mammals, and in some cases even con- vulsions are stated to have occurred in quinine poisoning, although these are so rare that the suspicion is aroused that the preparation was contaminated with cinchonidine or some other alkaloid. Cinchonidine seems the most poisonous of the four chief alkaloids, quinine following next, and then cinchonine and quinidine. PREPARATIONS. U. S. P. Cinchona, the bark of Cinchona calisaya and of C. officinalis and of hybrids of these and of other species of Cinchona, yielding not less than 5 per cent, of total alkaloids and at least 2.5 per cent, of quinine. Cinchona Rubra, red cinchona, the bark of Cinchona succirubra, contain- ing at least 5 per cent, of alkaloids. Fluidextractum Cinchonce, 4 c.c. (1 fl. dr.). TINCTURA CINCHONA, 4-15 c.c. (1-4 fl. drs.). TINCTURA CINCHONJE CoMPOSiTA is the only preparation of red cinchona, and contains in addition serpentaria and bitter orange peel. 4-15 c.c. (1-4 fl. drs.). These preparations of cinchona were formerly much more in vogue than at the present day, in which they have been replaced for most purposes by the 1 Further investigation regarding the fate of quinine in the human tissues is desir- able, since Merkel has found that seven-eighths of that administered to dogs is com- pletely oxidized and the remaining eighth undergoes extensive chemical change. QUININE. 363 alkaloids. They are still prescribed alone or together with other remedies as stomachic bitters. QUININA, SULPHAS, 0.3-1 G. (5-15 grs.) ; to be increased when necessary. Quinince Bimlphas, Quinince Hydrobromidum, QUININE HYDROCHLORIDUM, Quinince Salicylas (U. S. P.), Oleatum Quinince (U. S. P.), Ferri et Quinince Citras, 0.3-0.6 G. (5-10 grs.). Ferri et Quinince Citras Solubilis, 0.3-0.6 G. (5-10 grs.). Syrupus Ferri, Quinince et Strychnince Phosphatum, Easton's syrup, 4 c.c. (1 fl. dr.). Cinchonince Sulphas j Q ^ g G (8 _ 20 }> Cinchomdince sulphas, j Elixir Ferri, Quinince et Strychnince Phosphatum, 4 c.c. (1 fl. dr.). Glyceritum Ferri, Quinince et Strychnince Phosphatum, 1 c.c. (15 mins.). B. p. Cinchona Rubrae Cortex, red cinchona bark, the dried bark of the stem and branches of Cinchona succirubra. It ought to contain 5-6 per cent, of total alkaloids, of which one half should consist of quinine and cin- chonidine. Extractum Cinchonse Liquidum, 5 per cent, of alkaloids, 5-15 mins. TINCTURA CINCHONA, 1 per cent, of alkaloids, |-1 fl. dr. TINCTURA CINCHONA COMPOSITA, containing bitter orange peel, serpen- tary and coloring matters, -1 fl. dr. Infusum Cinchonse Acidum, containing aromatic sulphuric acid, ^-1 fl. oz. QUININE HYDBOCHLORIDUM, 1 Quininse Hydrochloridum Acidum, > 1-10 grs. QUININE SULPHAS, ) Tinctura Qulninse, formed from the hydrochloride and flavored with orange, -1 fl. dr. Tinctura Quininse Ammoniata, formed from the sulphate, J-l fl. dr. Vinum Quininee, J-l fl. oz. Pilula Quininse Sulphatis, 2-8 grs. Syrupus Ferri Phosphatis cum Quinina et Strychnina, Easton's syrup. Each fl. dr. contains i gr. of quinine sulphate and & gr. of strychnine. \-\ fl. dr. Ferri et Quininse Citras, 5-10 grs. (See Iron.) Quinine is practically insoluble in water and several of its salts are only dis- solved sparingly. Thus, the sulphate requires 800 times its own weight of water, the hydrochlorate 35, the hydrobromate 54, and the valerianate 100. The presence of acid in excess renders them much more soluble, and the acid hydro- chlorate is dissolved in less than its own weight of water, the bisulphate in 10 parts. They all form crystalline powders with a very bitter taste, and their solutions in water have a blue fluorescence when sulphuric acid is present. The acid hydrochloride and the bisulphate have an acid reaction, the others are neutral. The sulphate of quinine is the salt generally prescribed, although the hydro- chlorate is more soluble and ought to be preferred. The hydrobromate and vale- rianate are comparatively seldom used. Instead of the acid salts being pre- scribed, some sulphuric acid or hydrochloric acid may be ordered to be added to the neutral salts in order to facilitate their solution. The salts of quinine are frequently given in the form of pills, cachets, tablets, or capsules, which have the advantage of avoiding the bitter taste, but from which the alkaloid is more slowly absorbed than from solutions. Care must be taken that the pills are soft and freshly prepared, as when kept for any length of time they become hard, and in this condition frequently pass through the bowel unabsorbed. The salts or the pure alkaloid may also be given as powders, or the former in solution, but these are objected to by many patients on account 364 ORGANIC DRUGS ACTING AFTER ABSORPTION. of the bitter taste. When a rapid absorption is desired, solutions should be used, flavored, if necessary, with syrup and volatile oils. Solutions of the salts are occasionally injected as enemata, but are liable to set up irritation and be rapidly evacuated. The hypodermic method has also been advised in cases of emergency, or where the salt cannot be retained or absorbed from the stomach ; for this purpose a solution of the hydrochlorate with hydrochloric acid in excess or of the sulphate is injected deeply into the muscular tissue. This form of medication is painful, but does not seem to induce more serious results if ordi- nary care is used. The neutral hydrochlorate may be dissolved in hot water and injected when the solution reaches body temperature with less pain than is elicited by other salts. In this way about two parts of water are required to dissolve one of quinine. The addition of urea to the solution renders it less irritant. Quinine is very easily dissolved in water when it is mixed with anti- pyrine in the proportion of three parts of quinine to two of antipyrine, and this solution is said to be less painful when it is injected hypodermically than others. The intravenous injection of quinine has been practised by Baccelli with success in cases of pernicious malaria. He uses the hydrochlorate in a solution of com- mon salt and injects into one of the veins of the arm. Many other salts of quinine have been proposed, and have enjoyed a certain reputation for some time. Among the better known of these is the tanna.te, which is exceedingly insoluble and almost tasteless, and is prescribed in powder in doses of 1-3 G. Other salts which have been recommended are the tar- trate and the lactate. Euquinine is the ethyl-ether of quinine-carbonic acid (CO(OC 2 H 5 )(OC 20 H 23 N 2 O)) and is said to possess the therapeutic virtues of qui- nine without its bitter taste and without inducing ringing in the ears and other symptoms. Aristochme (CO(C 20 H 23 N 2 O) 2 ) and Chinaphenine (CO(NH- C 6 H 4 - OC 2 - H 5 )(OC 20 H 23 N 2 O)) are compounds of quinine of a similar nature recently intro- duced. All three preparations are prescribed in powder or tablets, in the same dose as quinine. A famous preparation of quinine is Warburg's tincture, which has been exten- sively used in India in the treatment of malaria. It contained a very large number of ingredients, many of which were certainly entirely superfluous. Among the more important constituents were aloes, rhubarb, gentian, camphor, and various volatile oils ; it is possible that some of these may have aided the quinine through their effects on the stomach. Various drugs, such as capsicum and piperine, have long had some reputation as adjuvants in quinine treatment for a similar reason. The other alkaloids have been used occasionally as substitutes for quinine, but have somewhat less therapeutic effect, while cinchonidine is more liable to produce symptoms of poisoning. They might all be dispensed with, without loss to therapeutics. Quinoidine and qulnetum were formerly used as substitutes for quinine at a time when the price of the latter was very high. They were mixtures of the other cinchona alkaloids and have fallen into disuse. Therapeutic Uses. The introduction of cinchona into therapeutics was due to the discovery of its efficacy in ague or Malaria, and with growing experience in the disease and its treatment, the confidence in the drug, or rather in its chief alkaloid, has constantly increased, until the action of quinine in malaria is now quoted as the best example of a specific in therapeutics. The explanation of its action has only been arrived at within the last few years with the discovery of the cause of malaria, the plasmodium malarise, although in 1868 Binz suggested that the then unknown malarial poison was probably rendered inert by quinine. The plasmodium belongs to the group of protozoa, and in one of its stages comes to resemble somewhat the amoeba, on which QUININE. 365 Binz experimented. The effect of quinine seems similar in the two organisms, although it is probable that the alkaloid acts more strongly on the malarial organism in the blood than on the common amoeba living in water ; another organism closely related to that of malaria and found in the blood of birds appears to be unaffected by quinine. When quinine is administered to a patient suffering from malaria, the organism in the blood breaks up and disappears, leaving only a few more resistant forms ; these, however, may continue to grow and mul- tiply until they cause a second attack, unless the treatment be continued and the surviving organisms, changing into less resistant forms, are destroyed by the drug. In a drop of malarial blood the plasmodia may be seen in active movement, but a minute drop of quinine solution paralyzes and kills them, exactly as it kills the amoeba. The explanation of the action of quinine on malaria lies in its effects as a protoplasmic poison, therefore, which acts more strongly (specifically) on the lower forms of life than on the higher, and can consequently be introduced into the human body with impunity in doses which are destructive to the simpler organisms Fio. 34. BOOKS 105' KU Temperature chart in a case of malaria in which quinine (10 grains) was administered in the third paroxysm as the temperature was falling. On the following day no rise of temperature occurs. The te'uiperature was taken every three hours. (DOCK.) which may have invaded it. Experience has shown that quinine is most effective when it can act immediately after the paroxysms of ague, and this is now explained by the fact that the organisms are in their least resistant form the amoeboid at this time. If quinine is given at the beginning of an attack, sufficient will remain in the blood when the temperature begins to fall to destroy the unprotected spores of the parasite, or the same result may be obtained by a dose given as the temperature begins to fall provided the drug is rapidly absorbed, 366 ORGANIC DRUGS ACTING AFTER ABSORPTION. as is ordinarily the case. It may be ordered in one dose of about 1 G. (15 grs.), or in divided doses given at intervals during the fall of the temperature. This frequently prevents the next attack, but if any rise of temperature occurs, a smaller dose should be administered. After this a dose of 1 G. should be given every six days, in order to com- plete the destruction of the organisms which have developed from the resistant forms left alive after the first administration. Quinine is generally administered by the mouth in malaria, but its intensely bitter taste renders this treatment disagreeable, and in children and in cases of persistent vomiting it may be impossible ; in such circumstances it may be given in an enema or suppository, or in children the tasteless forms may be employed. In recent years good results have been ob- tained by the hypodermic method, and in the severe form known as pernicious malaria, Baccelli found the intravenous injection superior to any other method of administration. A great deal of weight was formerly laid on the use of purgatives and emetics as preliminaries to the treatment of malaria with quinine, and the former are undoubtedly of service sometimes, although it is unnecessary to delay the quinine treatment by waiting for the intestines to be evacuated. Quinine is used not only as a remedy, but also as a prophylactic against malaria. Its value for this purpose has been attested by long experience, but there is still no unanimity of opinion as to the best method of administration and the dose required. Plehn found that one gramme of the sulphate given in one dose every seven days was sufficient to prevent the disease, which is believed to have an incuba- tion period of a week, while others recommend doses of 0.1-0.2 G. (2-3 grs.) every morning. One of the results of quinine medication in early cases of malaria is the reduction of the enlarged spleen, and this has led to its use in other Diseases of the Spleen with enlargement. In malaria the effect on the spleen is only secondary to the removal of the cause of the dis- ease, but the action of quinine in lessening the number of leucocytes in the blood might explain some alteration in the spleen. In some cases of leucsemic enlargement encouraging results have been obtained from the continued use of quinine. Various other Febrile Conditions have been treated with quinine, partly for the sake of its antipyretic effects and partly in the belief that it acts as an antiseptic in the blood. As regards its effect on the temperature in non-malarial fever, it not infrequently causes a con- siderable fall, and has the advantage of possessing a more prolonged action and of causing less risk of depression and collapse than the newer antipyretics. On the other hand, the fever is not reduced so rapidly and generally not to the same extent as by the latter, and the large quantities of quinine required are liable to cause discomfort from their effects on the brain and hearing. Typhoid fever, scarlatina and other acute pyrexias are sometimes treated with quinine for this effect. The best results are obtained when it is exhibited in maximal doses when the temperature is falling or when it has been temporarily reduced by QUININE. 367 other means, such as cold baths. Perhaps, however, the beneficial ac- tion of quinine in those cases ought to be measured not so much by the reduction of the body temperature as by the lessened destruction of the tissues. It would be interesting to know whether in those cases in which quinine treatment is successful, the nitrogen of the urine is diminished in proportion to, or in excess of the fall of the tempera- ture. In general, antipyrine and its allies have succeeded in ousting quinine from its former position as the best of the antipyretics. The use of quinine has been recommended in septicaemia, largely from a belief in its antiseptic action in the blood. In this connection it is to be remarked that the microbes of septic fever are very much more resistant to the action of quinine outside the body than are the pro- tozoa, and the question therefore arises whether the blood and tissues are not liable to be seriously injured by the quantity of quinine re- quired to act on the parasites they contain. In many cases of septi- ca3mia in which beneficial results are said to have been obtained by the use of quinine, the quantity administered was obviously too small to have any effect either on the temperature or on the microbes. Quinine has been used in various forms of Neuralgia and Headache, especially when they were periodic in their appearance, and good re- sults nave been obtained in these cases and also in others where no periodicity could be observed. Many of these were certainly not of malarial origin, and no explanation of the action of quinine here has been proposed. Perhaps the lessened formation of uric acid and other poisonous products may be suggested as a possible cause of the im- provement. The tinctures of cinchona are often prescribed as stomachic bitters and for .this purpose are generally fortified by preparations of nux vomica or of the simple bitters. Quinine has been advised in whooping-cough, hay fever and in- fluenza, and in fact is regarded by many as a specific in these diseases, though others have found it unreliable. It is often difficult to induce a child to take the bitter salts, and recourse may be had to the alka- loid itself, euquinine, or the tannate disguised with sugar or chocolate. The use of a solution as a wash for the nose in hay fever was brought into prominence by Helmholtz, who gained relief in this way, but it has not proved very efficacious. The local use of quinine solu- tions and of cinchona preparations is also advised in relaxed throat (gargle) and in gonorrhoea (urethral injection). It has sometimes been used as an antiseptic externally, but is too expensive for ordi- nary use. Quinine has been advised as an ecbolic to increase the contractions of the uterus during labor. This was suggested by the observation that in malarial regions, abortion occasionally occurred after quinine, but many regard this as one of the rarer idiosyncrasies rather than as a fact upon which the therapeutic use of the drug is to be based. At the same time others report the most satisfactory results from the treatment of uterine inertia with one-gramme doses of quinine, and pre- 368 ORGANIC DRUGS ACTING AFTER ABSORPTION. fer it to ergot in this condition. The movements of the uterus induced are said to be practically identical with those occurring naturally. Contraindications. Where a special idiosyncrasy exists, quinine may be unsuitable, but these cases are far rarer than is generally believed. A moderate action on the hearing, for example, is not to be considered a contraindication, although in those cases a small dose is often found sufficient in malaria. Where an inflammatory condition of the mem- branes of the ear already exists, quinine ought to be administered with care, or avoided entirely if possible. The addition of bromides is often found to lessen or remove the discomfort arising from the dis- ordered hearing, but the quantity of bromide contained in the hydro- bromate of quinine is insufficient to effect this, and the ordinary potas- sium salt ought therefore to be prescribed. Where very marked disturbance of the digestion exists, quinine is often liable to augment it, owing to its irritant properties, and must therefore be given with cau- tion by the mouth, or perhaps, is better applied hypodermically. Ha3moglobinuria following the administration of quinine, of course, contraindicates its further use. Abortion so seldom occurs after qui- nine that pregnancy is no objection to its administration. In general, it may be stated that quinine is often credited with many disadvan- tages which it does not possess, and that in cases of malaria, in which it is practically without a rival or substitute, only the most pronounced idiosyncrasy can justify withholding it. In other cases, as in septic fever, it may be a question whether it does not aggravate the condition when it is administered to very weak patients. i BIBLIOGRAPHY. Binz. Arch. f. mikros. Anat., iii., p. 383. Virchow's Arch., xlvi., p. 67; li., p. 6. Experimentelle Untersuch. ueber das Wesen der Chininwirkung, Berlin, 1868. Arch, f. exp. Path. u. Pharm., i., p. 18; v., p. 39 ; vii., p. 275. Wild. Brit. Med. Journ., 1887, ii., p. 500. Cerna. Phila. Med. Times., x., p. 493. Wood. Therap. Gazette, Jan., 1902. (Skin Eruptions.) Wittonaack. Pfliiger's Arch., xcv., pp. 209, 234. Husemann. Therap. Monatsheft., 1888, p. 7. Appert. Virchow's Arch., Ixxi., p. 364. Gottlieb. Arch. f. exp. Path. u. Pharm., xxvi., p. 419 ; xxviii., p. 167. Hertwig. Jena. Ztschr. f. Med. u. Naturwiss., xx., pp. 120 and 477. Merkd. Arch. f. exp. Path. u. Pharm., xlvii., p. 165. Santesson. Arch. f. exp. Path. u. Pharm., xxx., pp. 411 and 448 ; xxxii., p. 321. Skand. Arch. f. Physiologic, vii., p. 385. Webe?\ Ergebnisse der Physiologic, iii. 1, p. 262. (Metabolism.) Loevri. Ibid., iii., 1, p. 360. (Temperature.) v. Noorden u. Zuntz. Arch. f. Anat. u. Phys., 1894, p. 203. Talma u. v. d. Weyde. Ztschr. f. klin. Med., ix., p. 276. Albertoni. Arch. f. exp. Path. u. Pharm., xv., p. 248. Schumacher. Arb. a. d. pharm. Inst. zu Dorpat, x., p. 1. See et Bochefontaine. Comptes rendus, xcvi., pp. 266 and 503 ; c., p. 644. Bochefontaine, Arch, de Phys., 1873, p. 389. Rossbach. Pharmakol. Untersuch., i., p. 145. Grethe. Deutsch. Arch. f. klin. Med., Ivi., p. 189. Maragliano. Ztschr. f. klin. Med., xiv., p. 309; xvii., p. 291. Liepelt and Stuhlinger. Arch. f. exp. Path. u. Pharm., xliii., pp. 151, 168. Hedbom. Skandin. Arch. f. Physiol., ix., p. 33. Pohl. Arch. f. exp. Path. u. Pharm., xli., p. 111. Hare. Therapeutic Gaz., 1897, p. 433. ACETANILIDE AND ANTIPYRINE SERIES. 369 De Schweinitz. Arner. Jour, of the Med. Scien., cxiv., p. 282. Cavazzani. Arch. Ital. de Biol., xxxii., p. 350. Ellram. Arch, internat. de Pharmacodyn. , ix., p. 289. (Cinchonamine.) Birch-Hirschfdd. Arch. f. Ophthalmol., lii., p. 358. Ward Holden. Arch, of Ophthal. and Otology, Nov., 1898. XXIII. THE ANTIPYRETICS. (ACETANILIDE AND ANTIPYRINE SERIES.) The antipyretics are a very recent addition to therapeutics, the old- est of this group now in use dating only from 1884. Up to 1875 the only means of combating high temperature were baths, vegetable alka- loids such as quinine and aconitine, or alcoholic preparations, but in that year Buss discovered that salicylic acid produced a fall in the fever temperature, and soon afterward carbolic acid and resorcin and its isomers were introduced as antipyretics. A very large number of antipyretics have been introduced since that time, but most of them have had only a temporary vogue, and those in general use at the present time are comparatively limited in number. Quinine is a quinoline derivative, and quinoline itself, as well as some of its simpler compounds, were among the earlier antipyretics suggested. Quinoline (C 9 H 7 N) was soon found to be dangerous from its producing collapse, but its derivatives Kairine (C 9 H 9 (OH)N C^, Kairoline (C 9 H g (CH 3 )(OH)NH) and Thalline (C 9 H 9 (OCH 3 )NH) were used extensively, although they have now been almost entirely abandoned. In fact the only quinoline bodies now used as antipyretics are Analgen and Thermifugine, which are still prescribed to a lim- ited extent. A new antipyretic was introduced in 1884 under the name of Antipyrine, which is derived from phenylhydrazine, and has proved superior to all of the earlier drugs. Phenylhydrazine (C 6 H 5 NH NH 2 ) produces a fall in the fever temperature, but this is frequently accompanied by collapse and changes in the blood, which prevents its use in medicine. Several of the simpler com- pounds, such as Pyrodine (acetylphenylhydrazine) and Antithermine (phenyl- hydrazine and Isevulinic acid), have received a more or less extensive trial as antipyretics, but have proved dangerous and inferior to Antipyrine, phenyl- dimethylpyrazolon, C 6 H 5 - N <^ H ^_~ ^^ ' The latter is still very largely used as an antipyretic, either in its original form or as a constituent of numerous combinations which have been introduced of late years. Among these may be mentioned Resopyrine (resorcin and antipyrine), Hypnal (chloral and antipyrine), Salipyrine (salicylic acid and antipyrine). Antipyrine early found a rival in Antifebrine or Acetanilide, which was advised as an antipyretic in 1886 by Cahn and Hepp. Aniline (C 6 H 5 NH 2 ), from which it is derived, has also some action on the temperature, but like phenylhydrazine producer dangerous collapse and destruction of the blood cells. Acetanilide (C 6 H 5 NHCOCH 3 ), the first of its derivatives to be intro- duced, is not entirely devoid of this poisonous action, and has been supplanted to a considerable extent by more complex and less poisonous bodies. One of these, Exalgine (C 6 H 5 NCH 3 COCH S ), differs from antifebrine only in possessing a methyl group in the side chain, and seems to resemble it closely in its effects. Another which enjoyed a short trial is Benzanilide (C 6 H 5 NHC 7 H 5 O), in which the acetyl radicle of antifebrine is replaced by benzoyl. It was soon found that both aniline and antifebrine underwent a partial oxidation in the body, 24 370 ORGANIC DRUGS ACTING AFTER ABSORPTION. with the formation of amidophenol or its derivatives, and the belief that the antipyretic effects were due not so much to the original substance as to these oxidation products led to the introduction of numerous derivatives of par- amidophenol l^e-^i^^jj ) ^his body has antipyretic properties but suffers under the same disadvantages as aniline. Among its derivatives the most sat- isfactory antipyretics are those in which the hydrogen of the hydroxyl is sub- stituted by an alkyl, while an acid radicle is added to the amido-radicle. The first of its compounds to be introduced was Phenacetine (C 6 H 4 lltr " t F ' g ' 33 ' at the lower temperature. In other words, the antipyretics reduce the tenaperature by increasing the output of heat, and the cells of the body grow and change less when removed from the hot-house temperature to which they have been exposed previously. It must be added, however, that sonic observers hold that the fall in heat formation is too great to be explained in this way, and suppose that the antipyretics lessen the 378 ORGANIC DRUGS ACTING AFTER ABSORPTION. combustion through some other action, but not by affecting the tis- sues directly. It has been stated already that the fevered animal resists any change in its temperature in the same way as the normal, and it might there- fore be expected that when the temperature is reduced by antipyretics the organism would at once increase its heat formation. The fact that this does not occur, but that, on the contrary, the metabolism is les- sened, indicates that some further change occurs, that the antipyretics not only reduce the temperature by allowing the heat to escape, but also alter the condition of the coordinating mechanism by which the temperature is kept uniform. To return to the comparison with a thermostat, the body temperature is set at a lower point by the anti- pyretics, while it is set higher by the fever poisons. The action of the antipyretics on this coordinating centre is there- fore of interest, and has been examined both in health and disease. In healthy men the temperature does not undergo any marked change under the antipyretics for though it may fall a few tenths of a degree in some cases, this is of no significance. The sensitiveness of the coordi- nating centre is increased apparently, however, for in some individuals in whom hard muscular work causes a rise of temperature normally, this is absent or less marked after the antipyretics. In the same way the rise of temperature which occasionally is caused by very hot baths, is absent or diminished when antipyrine has been administered pre- viously. When the basal ganglia are cut off from their connections with the lower part of the body, neither septic injections nor antipy- retics have any effect on the temperature, while after section above the basal ganglia, fever is caused, and the antipyretics induce the usual fall of temperature (Sawadowsky). In experiments in which a high fever was produced by lesions in the neighborhood of the ganglia, Gottlieb found that the antipyretics reduced the temperature and in- creased the output of heat to a marked extent, while the formation was increased to a less degree. Finally, the condition of the centre has been examined by Stern and Kichter after the temperature had been reduced by antipyretics. They both found that the protective mechanism was called into play when the temperature was slightly raised, and generally when it was depressed. For example, a fevered dog (temperature 40.9 C.) re- ceived a dose of kairine, and its temperature was reduced to 37.6. Attempts were now made to raise the temperature by external heat, but the animal resisted this by increasing the output as soon as the tem- perature rose to 37.8. The coordination which maintained the tem- perature at 40.9 before the drug was administered now attempted to keep it at 37.6. The results of these researches may be summed up shortly as fol- | lows : The antipyretics reduce the temperature in fever through alter- ations effected in the heat-regulating nervous mechanism, wHich result in lowering the point at which the temperature is maintained. As a couse- ,-..rw,*.**'W'*** 1 : "' ''^-^^"' "* ""--'-* ACETANILIDE AND ANTIPYRINE SERIES. 379 38 37 36 35 34 33 31 P I quence of this action, a great increase in the dissipation of heat must occur in order to free the body from, the warmth which it has accumu- lated, and this increased output is attained by dilatation of the FIG. 36. cutaneous vessels. The seat of action of the antipyretics is probably situated in the base.,of the cerebrum. The precise nature of the changes wrought by the antipy- retics in the coordinating mech- anism is unknown. Gottlieb and Harnack suggest that it is depressed by them and this would accord with the widely held idea that fever temperature is due to some form of brain ir- ritation ; but their reasoning is open to objection, and specula- tion seems useless until more 30 is learned regarding; the normal . & Curve of the internal temperature (unbroken function Ot thlS Organ. line) and of the skin temperature (dotted line) in ^ TT , ,, . , fever treated with antipyrine (Roseuthal). The ab- When the temperature IS de- scissa AS represents the time in hours, the vertical, pressed too rapidly by these ^ S!Tffffto S^^^E^ remedies, a condition of collapse is often produced, while in other cases the loss of heat caused by the dilatation of the skin vessels seems to be excessive, and shivering and rigor follow in order to increase the production. When the temperature has reached the new point fixed by the coor- dination under the influence of the antipyretic, the heat dissipation rapidly diminishes and may become less than normal, because the new temperature is maintained at a constant point by the same mechanism as the normal. The antipyretics are rapidly absorbed, and as rapidly Excreted by the kidneys, so that they disappear from the body within 24-30 hours after their administration. The fate of antipyrine seems to differ in different animals. In the dog it is found to be partially oxidized to oxyantipyrine which is excreted in the urine in combination with glycuronic and sulphuric acids. In others it is said to be excreted in the urine unchanged. Antifebrine undergoes a partial oxidation, the final product differing in different animals, but none of the original body appears in the urine except after very large doses. In man it appears as acetylparamidophenol (C 6 H 4 < O TT 2 3 ) and as paramidophenol or another of its compounds, both being in combination with sulphuric and glycuronic acids. In the rabbit's urine paramidophenol alone is found, while in the dog this is accompanied by oxycarbanil (C 6 H 4 < > CO) ; in each case it forms a double sulphate or glycuronate. The fate of the other anti- temperature fel1 again as the 380 ORGANIC DRUGS ACTING AFTER ABSORPTION. pyretics resembles that of antifebrine, the quinoline derivatives undergoing a partial oxidation resulting in a body analogous to paramidophenol, while the phenetidine compounds are partially decomposed and appear in the urine as glycuronates of pheuetidine. The combinations containing salicylic acid break up in the body, and the acid appears in the urine as salicyluric acid, while the rest of the molecule undergoes the usual partial oxidation. The presence in the urine of these bodies, or rather of further pro- ducts of their oxidation, gives it a dark reddish-brown color, which may be observed when it is passed, or more frequently after it has been ex- posed to the air for some time. PREPARATIONS. ACETANILTDUM (U. S. P., B. P.), acetanilide or antifebrine. Acetanilide is a colorless, crystalline body insoluble in water, soluble in alcohol, ether and chloroform. It has no odor when pure, but has a slight burning taste. It may be prescribed in powder, suspended in mucilage, or in cachets or lozenges. The B. P. gives as the dose 0.06-0.2 G. (1-3 grs.), but it is often given in larger doses, up to 0.6 G. (10 grs.). Pulvis Acetanilidi Compositus (U. S. P.) contains 7 parts of antifebrine, 1 of caffeine, and 2 of sodium bicarbonate. Dose, 0.5 G. (7 grs.). ANTIPYRINA (U. S. P.), PHENAZONUM (B. P.) phenazone, or ANTIPYRIKE, forms colorless inodorous crystals, with a bitter taste, very soluble in water, alcohol and chloroform. 0.3-1.3 G. (5-20 grs.). PHENACETINUM (B. P.), ACETPHENETIDINUM (U. S. P.), colorless, tasteless crystals, insoluble in water, 0.3-1 G. (5-15 grs.), in the same forms as acet- anilide. Non- official. Thalline is generally seen as thalline sulphate, a colorless crystalline sub- stance, of a weak aromatic odor and slightly bitter taste, soluble in 7 parts of water. 0.2-0.5 G. (3-8 grs.). Exalgine resembles acetanilide except in its greater solubility in water, and may be given in the same quantity. Malakine, Lactophenine, Thermodine, Neurodine, Saliphen and Salophen all resemble each other in being insoluble in water, colorless and crystalline, and are prescribed in the same way as acetanilide and, in doses of 0. 5-1 G. Phenocoll is generally used as the hydrochlorate, which is fairly soluble in water, while Salocoll is insoluble. 0.5-1 G. (8-15 grs.). Malakine, Saliphen, Salocoll and Salophen all break up in the body, freeing salicylic acid, so that, in addition to the antipyretic action, the characteristic effects of this acid may be elicited by them. The antipyretics are almost invariably given by the mouth. Antipyrine has been injected hypodermically, but is somewhat painful, because much larger quantities have to be used than are generally given by this method, and the solutions have, therefore, to be more concentrated (30-50 per cent.). Therapeutic Uses. The antipyretics are used chiefly to Reduce the Fever Temperature. The most satisfactory results are obtained from those which act somewhat slowly, but which preserve a low temperature for some time, and antipyrine and the phenetidine compounds are thus preferable to the earlier remedies, which produce a more abrupt fall, after which the temperature soon regains its former height. The best effects are obtained when the antipyretic is given at the commencement of a natural remission, the temperature often falling 24 degrees in the course of the next 23 hours, and only rising slowly afterwards. In some ACETANILIDE AND ANTIPYEINE SERIES. 381 fevers the antipyretics have much less tendency to lower the tempera- ture than in others. Thus in septicaBmia larger doses are required than in typhoid and not infrequently no satisfactory reduction of the tempera- ture follows the administration of the maximal quantity. Pneumonia is also said by some writers not to be affected so easily as some other febrile conditions in which the heat-regulating centre appears to be in a less stable condition, as is manifested by the occurrence of large spon- taneous variations of temperature. The reduction of the temperature by the antipyretics lasts only as long as the drug is present in sufficient quantity in the body, and accordingly as soon as sufficient has been excreted, the intoxication of the regulating mechanism begins again, and the temperature soon rises to its former height. The antipyretics do not act on the cause of the disease, but only remove one of the symptoms, but this in itself is not an argument against their use, as is apparently believed by some writers, because as long as the physician is unable to treat the cause directly, he is justified in taking such measures as are possible to remove the symptoms, rather than in adopting an ex- pectant treatment, pure and simple. The extensive use of these reme- dies shows very clearly that the high temperature is merely a symp- tom of disease, and not the disease itself, and the question has been much debated as to whether the reduction of fever is in any way bene- ficial. No one questions that some antipyretic measures should be taken when the temperature rises so high as to form a danger in itself, but their use in ordinary fever cases is more doubtful, and many physicians deprecate their use unless in exceptional cases. The very large doses formerly used undoubtedly induced dangerous symp- toms occasionally, but there is little risk of this occurring from the intelligent, use of the less violent members of the series. It has recently been shown by Schutze and Beniasch that the use of the antipyretics does not retard the formation of the protective substances (antitoxins) to which the recovery from fever is attributed, for in infected animals treated with enormous quantities of antipyrine the serum displayed the same agglutinating properties towards the bacilli as that of controls which were not subjected to any medication. A more serious argument against their use in fever is that the course of the disease is less readily followed, because one of the guiding symp- toms the temperature variations is no longer dependent solely upon the severity of the intoxication with the fever poisons, and both diagnosis and prognosis are thus rendered more difficult. For example, in typhoid fever a sudden fall of temperature often gives the first in- dication of such a complication as hemorrhage, but if an antipyretic has been given beforehand, this indication may be entirely absent. On the other hand, it is urged in favor of the antipyretic treatment that the patient feels more comfortable and easier when the temperature is reduced, and that this alone may favorably influence the course of the disease. Besides, the high temperature in itself increases the tissue waste, and causes larger draughts on the resources of the patient than would be made with the same amount of poison in the tissues at a 382 ORGANIC DRUGS ACTING AFTER ABSORPTION. lower temperature ; and although the influence of the high temperature on the metabolism was undoubtedly exaggerated at one time, this con- sideration is by no means devoid of weight. The theory that fever is a defensive measure taken by the organism against the causes of dis- ease and ought not to be interfered with therefore, is now seldom men- tioned. The antipyretic treatment of fever is of value, then, in cases where the temperature is so high as to endanger life, in cases in which the rise of temperature is the chief cause of distress and no complica- tions are to be apprehended, and, in general, in cases in which the increased comfort of the patient is not counterbalanced by their ob- scuring the diagnosis and prognosis. On the other hand, there is no reason to suppose that it lessens the mortality or shortens the course of most fevers, or that it prevents complications of any kind except excessively high temperature, and the routine treatment of fever with antipyretics is to be deprecated. The chief rival of the antipyretics in the treatment of fever in the present day is the so-called cold-bath treatment, in which the fever patient is bathed frequently in water the temperature of which varies from 70-90 F. in different hospitals. The temperature generally falls to a considerable extent under this treatment, and very often a general improvement in the symptoms occurs. The effect on the temperature is mainly due to the abstraction of heat from the body, and thus far corresponds to that of the antipyretics. In the cold-bath treat- ment, however, the loss of heat is not immediately due to the dilata- tion of the skin vessels, for baths at 70 F. have rather the effect of constricting the vessels primarily, whatever may be the sub- sequent effect. The heat output increases here from the change in the external medium, and not from any alteration in the skin itself. The fall of temperature is generally not so great as under the anti- pyretics, and the regulation is not directly affected, for the patient shivers and becomes cyanotic long before the normal temperature is reached. The therapeutic virtue of the cold bath was formerly believed to lie exclusively in the abstraction of heat and the fall of temperature, but many advocates of the treatment now hold that this is of less im- portance than the effects on the circulation and the brain, which are elicited reflexly by the cold water applied to the skin, and which are not now believed to be due to the fall in temperature. Whether this view is correct or not, the whole nature of the fall in temperature is different from that produced by the antipyretics, and the metabolism, instead of becoming less active as it does under the latter, rather tends to increase under the cold baths, at least as far as the tissue change can be measured by the nitrogen excreted. The relative therapeutic value of the two methods of treating fevers can only be determined by clin- ical experiment, and the present attitude of the clinicians, which tends to favor the cold-bath treatment, may be reversed in course of time. However the matter may stand in hospital practice, in which trained assistance is available, the antipyretics have a great advantage in many cases in which treatment has to be carried out without any such faciK- ACETANILIDE AND ANTIPYRINE SERIES. 383 ties, for the administration of these drugs may, of course, be entrusted to ordinary persons, whereas the cold bath can be given only by the physician himself or by trained attendants. Particularly in the milder fevers, where no complicated measures, such as the cold bath, are considered necessary, the antipyretics give relief to the patient by removing the feeling of heat and discomfort. Other antipyretic drugs are quinine, aconite, digitalis, and alcohol, but none of these produce an equal fall of temperature unless with the presence of alarming and dangerous symptoms. Aconite and digitalis are generally supposed to reduce the temperature through their effects on the circulation, although it is not impossible that they may also affect the centres for heat regulation. Quinine acts probably through reducing the metabolism, and alcohol by dilating the skin capillaries, and perhaps by lessening the movements and thereby the formation of heat. All of these drugs are used very much less as antipyretics now than formerly, as, besides their undesirable secondary effects, the fall of temperature is less certain and less profound than under the modern antipyretics. The antipyretics are also used very largely to relieve Neuralgic Pain and Headache, often with complete success. So little is known re- garding the pathology of these diseases that it would seem premature to discuss the method in which these remedies act. By many they are supposed to have a sedative or depressant effect on the central nervous system, but this must be limited in its range, for quantities sufficient to remove pain often leave the mind perfectly clear. The analgesic action of these bodies is apparently quite different from that of mor- phine, for in many instances in which the latter is successful they fail to alleviate the condition. On the other hand antipyrine and its allies can often be used where morphine is contraindicated, either from the danger of the habit being formed, or from the somnolence it induces. The antipyretics appear to be of little or no value in relieving the pain caused by acute inflammatory conditions, while on the other hand they are almost specific in some neuralgic cases. Almost all of the antipyretics are efficient in these cases, but larger doses are generally required than to reduce fever, and the more powerful, such as antifebrine, are often preferred to the safer and more slowly acting phenetidines. Caffeine is often prescribed along with the antipyretic, as in the compound acetanilide powder. Several of the antipyretics have been used as Substitutes for Quinine in the treatment of malaria, but none of them seem to have the specific action of the latter on the organism of malaria, and, although they may reduce the temperature, they do not prevent the other symptoms and do not remove the cause of the disease. In the same way they do not seem to equal salicylic acid in efficiency in acute rheumatism, although here again they reduce the temperature. This does not apply, of course, to those of the antipyretics, such as malakine, which form salicylic acid in their decomposition in the body. It is to be noted that the amount of salicylic acid thus formed from the ordinary dose 384 ORGANIC DRUGS ACTING AFTER ABSORPTION. of the antipyretics, is considerably smaller than would be given if the acid itself were prescribed. The antipyretics are used to a considerable extent in cases of dia- betes insipidus and mellitus and appear to relieve the discomfort and in some cases to improve the general condition. In whooping cough antipyrine often lessens the severity of the attacks and also renders them less frequent, and is said to shorten the course of the disease. The use of antipyrine and other members of this series as sedatives in hyperactivity of the motor functions of the brain, such as epilepsy and chorea, has not been attended with great success, although temporary im- provement has occasionally been noted, as after so many other remedies. Antipyrine and several others of this series have been advocated as local sedatives or anEesthetics, and have been used occasionally to lessen the irritability of the throat and larynx and thus to permit of the minor manipu- lations of laryngology. Holocaine, a body closely related to phenacetine, has been employed to a limited extent as a local anaesthetic in ophthalmol- ogy, but appears to be more poisonous than other equally efficacious drugs, such as eucaine. Thalline has been advised as a urethral injection in gonorrhoea. The occurrence of collapse and other symptoms has led to a consid- erable amount of distrust of the antipyretics among many of the med- ical profession. In justice it has to be remembered that in many cases these symptoms were produced only by very large doses, and that since experience has shown that beneficial results may be obtained by smaller quantities, these cases have notably diminished in medical practice. Unfortunately, this distrust is not entertained by a large class of the laity, and numerous cases of poisoning arise from the im- pression that the antipyretics are not dangerous drugs. For the most part, poisoning seems to be due to a peculiar sensitiveness or idiosyn- crasy, which cannot be foreseen, but in cases of great exhaustion and asthenia, especially when accompanied with anemia, these drugs have to be used with great care or avoided entirely'. BIBLIOGRAPHY. Umbach. Arch. f. exp. Path. u. Pharm., "xxi., p. 161. Riess. Ibid., xxii., p. 127. Sawadowsky. Centralbl. f. med. 'Wiss./ 1888, p. 145. Martin. Therap. Gazette, xi., 1887, p. 289. Lepine u. Porteret. Comptes rendus, cvi., p. 1023, and cvii., p. 416. Jaffe u. Hilbert. Ztschr. f. physiol, Chem., xii., p. 295. Morner. Ibid., xiii., p. 12. Loewi. Ergeb. der Physiologic, iii., 1, p. 365. Nencki. Arch. f. exp. Path. u. Pharm., xxx., p. 306. v. Mering. Therap. Monats., 1893, p. 577. Hinsberg u. Treupel. Arch. f. exp. Path. u. Pharm., xxxiii., p. 216. Treupel. Deutsch. med. Woch., 1895, p. 222. Pellacani. Arch. Italien. de Biologic, viii., p. 76. Lepine. Kevue de Medicine, 1887, p. 306. (John u. Hepp. Berl. klin. Woch., 1887, p. 4. Filehne, Liebermeister, etc. Congress f. inn. Med., 1885, pp. 118-185 ; 1896, pp. 3-100. Kumagawa. Virchow's Arch., cxiii., p. 134. Hinsberg u. Kast. Centralbl. f. d. med. Wiss., 1887, p. 145. (Phenacetine.) Maass. Zts. f. klin. Med., xxviii., p. 139. (Analgen.) ANTISEPTICS OF THE AROMATIC SERIES. 385 Filehne. Berl. klin. Woch., 1882, p. 681 ; 1883, p. 77. Stern. Zts. f. klin. Med., xx., p. 82. Hildebrandt. Virchow's Arch., cxxi., p. 1. Eichter. Ibid., cxxiii., p. 118. C. Rosenthal, Arch. f. Anat. u. Phys., 1888, p. 1. W. Rosenthal. Ibid., 1893, Suppl., p. 243. Simon and Hock. Johns Hopkins Hospital Bulletin, 1890. Maragliano. Ztschr. f. klin. Med., xvii., p. 291, and xiv., p. 309. Evans. Therap. Gaz., 1887, pp. 237 and 379. Gottlieb. Arch. f. exp. Path., xxvi., p. 419, and xxviii., p. 167. Kraus. Wien. klin. Woch., 1894, pp. 229 and 275. Harnack. Therap. Monats., 1894, p. 101. Fraenkel. Zts. f. klin. Med., xvii., Suppl., p. 239. (Pyrodine.) E-iedel. Zts. f. Heilkunde, xvL, p. 55. Penzoldt. Arch. f. exp. Path. u. Pharm., xxvi., p. 313. Liepelt u. Stuhlinger. Ibid., xh'ii., pp. 151 and 168. Tappeiner. Ibid., xxviii., p. 295, and xxx., p. 231. Heinz. Virchow's Arch., cxxii., p. 112. Schutze. Zeitschr. f. Hygiene, xxxviii.,p. 205. Beniasch. Zeitschr. f. klin. Med., xlv., p. 51. Laivrow. Zeitschr. f. phys. Chemie, xxxii., p. 111. Riethus. Arch. f. exp. Path. u. Pharm., xliv., p. 239. XXIV. ANTISEPTICS OF THE AROMATIC SERIES (CAR- BOLIC AND SALICYLIC ACID SERIES). Various balsams and wood-tar and some of its derivatives have long enjoyed a certain reputation in surgery, but the true value of the bodies of the aromatic series has only been realized since the systematic treatment of wounds with antiseptics was introduced by Lister some thirty years ago. The first antiseptic proposed by him was carbolic acid, and this held its position for several years, when it was discovered that bodies of similar origin, and others of entirely different composi- tion possessed equally great advantages as antiseptics with less liability to induce poisoning. Of late years a very large number of antiseptics belonging to the aromatic chemical series have been introduced, and have been discarded, often, it would appear, without sufficient exami- nation. It is not within the scope of such a work as this to examine all of these, especially as the effects of many of them differ only in detail, but the chief active principles will be mentioned. The great mass of the aromatic antiseptics are obtained from coal- or wood-tar by more or less complicated reactions, and are often known as the coal-tar or tar antiseptics. The hydrocarbons benzene or benzol, tolvol, xylol are too volatile for use as antiseptics, and the only hydrocarbon used for this purpose is Naphtalin(C 10 H 8 ). Among the hydroxyl compounds of benzol, Carbolic Acid or Phenol (C 6 H 5 OH) is the best known. The clioxybenzols (C 6 H 4 (OH) 2 ), three in num- ber, hydroquinone, pyrocatecftin, and resorcin have also been used in medicine, and resorcin was at one time a popular antiseptic, although it has latterly fallen into disuse. Among the trioxybenzols, Pyrogallol (C 6 H 3 (OH) 3 ) alone has been used extensively as an antiseptic in skin diseases, and is still considered of value in certain conditions. Hydroxyl derivatives of other hydrocarbons are the two Naphtols, a- and j3-, (C 10 H 7 OH) which are used as intestinal disinfectants. Thymol (C 6 H 3 (CH 3 )- 25 386 ORGANIC DRUGS ACTING AFTER ABSORPTION. (C 3 H 7 )OH), obtained from thyme, was introduced as a substitute for carbolic acid, but has fallen into disuse. More recently the cresols, C 6 H 4 (OH)(CH 3 ), of which three are known, have attained some prominence as antiseptics. The phenol ethers, anisol and phenetol (C 6 H 5 OCH 3 and C 6 H 5 OC 2 H 5 ) have never been introduced into therapeutic use, but guaiacol (CLH 4 (OH)(OCH 8 )), the methyl ether of pyrocatechin , has had some use of late years as an antiseptic and antipyretic. A combination of guaiacol and carbonic acid known as guaiacol carbonate (CO(OC 6 H 4 OCH 3 ) 2 ) has also been used. Other dioxy-derivatives are the creosols (C 6 H 3 (CH 3 )(OH)(OCH 3 )), which are im- portant constituents of wood-tar and of creosote. The substitution of chlorine for hydrogen in the benzol ring seems to in- crease its antiseptic power, and monochlorphenol (C 6 H 4 C1OH) and trichlor- phenol (C 6 H 2 C1 3 OH) have been suggested as antiseptics. A similar intensified action is obtained by the substitution of chlorine in the members of the methane narcotics. (See page 129.) The presence of the carboxyl group ( COOH) lessens the poisonous action of the aromatic series exactly as in the case of the methane series. Several acids have been suggested as internal antiseptics, therefore, and one of them, Salicylic acid (C 6 H 4 OHCOOH), is perhaps the most important of all the benzol compounds at the present time. Benzole acid (C 6 H 5 COOH) is an equally powerful antiseptic, but is comparatively seldom used as such. It is the chief constituent of several of the ll balsams," in which it is often accom- panied by cinnamic acid (C 6 H 5 CH=CHCOOH). Salicylic acid is the only one of three isomeric acids that has been found of value. It is used either as the pure acid or more frequently as the Salicylate of Sodium, or in the form of an ester. One of these, methylsal icy late, has long been known as the oil of wintergreen and as sweet oil of birch. Another well- known ester is the phenyl salicylate or Salol, (C 6 H 4 OHCOOC 6 H 5 ), while others of less widespread reputation are cresalol (salicylate of cresol), betol (salicylate of /3-naphthol), salithymol (salicylate of thymol). Several other salicylic compounds are used as antipyretics as well as for their action as salicylates and are mentioned among the antipyrine series. (Page 874.) The most recent substitute for salicylic acid is aspirin or acetylsalicylic acid (C 6 H 4 OC 2 H 3 O.COOH). Another acid which has been used as a substitute for salicylic acid is cresotinic acid (C 6 H 3 (CH 3 )(OH)(COOH)), and the oxynaphtoic acids (C 10 H 6 (OH)- (COOH)) have been suggested as antiseptics. Instead of carboxyl, the sulphon radicle has been attached to phenol in order to lessen its toxicity, and in this way the so-called sulphocarbolates were formed. They must be distinguished from the ether-sulphuric acids or double sulphates in which the HSO 3 is attached to the carbon of the ring by oxygen, while in the sulphocarbolates the connection between the OTT sulphur and the carbon is direct. (Sulphocarbolate of sodium, C 6 H 4 < Qn ^ sodium-phenol double sulphate, C 6 H 5 OSO 3 Na.) 3U 8 JNa, When two hydrogen atoms of the benzol molecule are substituted by other elements or radicles, three different chemical products may result, and these are known as ortho-, meta- or para-compounds, according to the relation the two substituted atoms bear to each other. These three isomeric forms very often differ in toxicity and also in their antiseptic power, but no general statement can be made as to their relative position, for the ortho- compound is sometimes the most powerful antiseptic, as in salicylic acid ; in others the meta-compound, as in metacresol, while parachlorphenol is more strongly antiseptic than either ortho- or metachlorphenol. Many crude preparations of these bodies are still in use and have the ad- vantage of cheapness over the pure principles, and are therefore preferred where disinfection has to be carried out on a large scale. Wood-tar varies in its composition with the wood from which it is ob- tained. The most important constituents are generally guaiacols and creo- ANTISEPTICS OF THE AROMATIC SERIES. 387 sols and their homologues, while carbolic acid and the cresols are less largely represented. Along with other only partially known substances, some hydrocarbons and acids such as acetic acid, also occur. Creosote is obtained from beech tar and consists chiefly of guaiacol and creosols with very little carbolic acid or cresol, which latter have a lower boiling point and are removed in the course of preparation. The volatile or ethereal oils have also antiseptic properties, and, in fact, no line of demarcation can be drawn between the volatile oil series and the antiseptics proper, for many bodies occur in both groups, and the great majority of the constituents of the volatile oil series belongs to the benzol compounds. The earliest antiseptics known were those occurring in plants, as is shown by the use of various herbs in embalming in Egypt. In later times several of the balsams, which contain benzoic and cinnamic acids dis- solved in volatile oils, were credited with beneficial effects in the treatment of wounds. Ichthyol is the ammonia salt of a sulphonic acid derived from the tar of a bituminous shale which is found in the Tyrol, and which contains the re- mains of many fossil fishes. The constitution of ichthyol is still doubtful and it is even undecided whether it is not really a mixture of a number of bodies. It contains a high percentage of sulphur, which seems to be only in part in the form of sulphons, in part in tha of mercaptans and sulphides. Thiol is an artificial product formed as a substitute for ichthyol by the action of sul- phur and afterwards of sulphuric acid on the tar obtained from brown coal. It seems to consist chiefly of sulphons, and is very soluble in water. Tumenol is another artificial substitute for ichthyol. Naphtalan is prepared from raw naphtha by distillation and is used instead of ichthyol. Action. The simpler bodies of the aromatic series produce symptoms in the living organism which present great similarity in their general features, although they differ in details. As a general rule it is found that the simpler members of the series are much more poisonous to the higher animals than the more complex ones, while the latter are equally or more efficient as poisons in the lowest living forms. They are all possessed of a more or less marked action on the central nervous sys- tem, which is entirely different from that of the methane narcotics, however. The brain and spinal cord are thrown into a condition of abnormal irritability, which is betrayed by an increase in the reflex movements and tremor and convulsions, and which is not due to the removal of inhibition as in the case of the methane compounds. Later, a stage of prostration and collapse is developed, which may simulate that seen in the narcosis of the fatty series, but does not seem to be identi- cal with it, for though in man the consciousness is often lost in this stage, the collapse in animals is in many cases not accompanied by loss of sensation or of the voluntary movements. The symptoms are gen- erally those of great muscular weakness and indicate depression of the vital centres of the medulla oblongata and of the heart rather than complete loss of the cerebral functions. They resemble surgical shock more than the anesthesia following the use of chloroform and ether, and are probably of a different nature from the latter. Many of the members of the benzol series tend to destroy the red cells of the blood and to form methaemoglobin ; this effect is especially developed in the case of pyrogallol and will be described under it in detail. Most of these antiseptics reduce the temperature in fever, 388 ORGANIC DRUGS ACTING AFTER ABSORPTION. while they have little effect on that of the normal body unless when given in large enough quantities to produce collapse. The cause of the fall of temperature in fever under the action of these drugs is not satisfactorily explained, although it seems probable that the process is the same as in the antipyrine series, with which they are nearly allied. The aromatic poisons differ from the typical members of the methane series in their effects on protoplasm in general. Alcohol and ether destroy life in all forms of protoplasm when they are brought in con- tact with it in sufficient concentration, but the phenols and acids of the aromatic series do so in more dilute solutions, and in fact owe their importance in medicine to their activity as general protoplasm poisons. Small quantities of the aromatic bodies seem to increase the activity of living matter, at any rate under some conditions, for the alcoholic fermen- tation is said to be accelerated by the presence of minute proportions of these poisons, and in the higher animals some of them increase the nitrogenous metabolism, while larger doses destroy the yeasts and also the tissues of the body. The evidence of central nervous irritation might also be cited in support of the view that the members of the aromatic series first accelerate and then retard protoplasmic activity, but the evidence is too limited as yet to admit of such a generalization. Therapeutic Uses. The members of the aromatic series are used in therapeutics chiefly as disinfectants and antiseptics, that is, to destroy or retard the growth of pathogenic and putrefactive microorganisms and yeasts. Their introduction by Lister to prevent the infection of wounded surfaces in surgery was followed by a revolution in surgical methods, which can only be paralleled by that which followed the in- trod uction of ansesthetics some twenty years earlier. The successful treatment of local infections by means of antiseptics encouraged the hope that general septic diseases might be as favorably influenced by them, but the two conditions are obviously entirely dif- ferent, for in the case of a local infection the remedy may be applied at the diseased point, and, although it may destroy the life of the superficial cells in the neighborhood, this is not of vital importance. On the other hand, a disinfectant, acting throughout the tissues of the body in sufficient quantity to destroy the microbes of infection, must have an equally unfavorable effect on the cells of the host, unless it has a specific action on the parasite, and this is very exceptional. A disinfectant in the strict use of the term is a substance used to destroy microbes, while an antiseptic, while not actually killing the germs, prevents their growth as long as it remains in contact with them. A disinfectant is accordingly only intended to act for a short time, for if the infected matter be once rendered sterile it can only become dan- gerous by being again contaminated. For example, a room requires only to be disinfected after a case of infectious disease. A wound, on the other hand, even though completely disinfected may become con- taminated again very easily and an antiseptic may be required to prevent the further growth of microbes. Many substances are disinfectant in ANTISEPTICS OF THE AROMATIC SERIES. 389 large quantities and antiseptic in more dilute solutions, but others are too weak to disinfect thoroughly though they retard the growth of pathogenic organisms, and still others may be employed to disinfect but are unsuitable for use as antiseptics, either because they are too poisonous to be applied for a sufficient time or because they lose their effects on the microbes (peroxide of hydrogen group). The uses of the antiseptics and disinfectants may be stated as follows : 1. To Disinfect Rooms, Furniture, Clothes, etc. For these purposes, the strongest and cheapest drugs which do not actually injure the objects may be employed. None of the aromatic series is very trust- worthy here, although carbolic solution has been employed ; the gaseous disinfectants, formaldehyde and sulphurous acid, are much more efficient. For the disinfection of the excrementa, crude carbolic acid and tar have been advocated. 2. To Prevent the Infection of Wounds in surgery. This was first attained by Lister's carbolic acid dressing and operative procedure, but many other antiseptics have since been substituted for carbolic acid, and the use of antiseptics during operations on uninfected organs has given \vay to the aseptic method. For use during operations on infected wounds, the disinfectant must be soluble or miscible in water, and ought to produce as little irritation as possible, but there is less likelihood of serious poisoning or irritation from the use of antiseptics here than from their subsequent application to the wounded surface as dressings. The importance of avoiding the use of irritant antiseptics in operations on delicate structures, such as the peritoneum, has only been fully recognized of late years. Where a dressing has to be applied for some time, and especially when the wounded surface is large, as in the case of burns or large abscesses, the danger of absorption has to be taken into consideration, and antiseptics ought therefore to be chosen which are either absorbed slowly or are not very poisonous to man. The frequent occurrence of more or less severe carbolic intoxication has led to its employment being much more restricted than formerly, while the less soluble or less poisonous antiseptics have taken its place. 3. In the Treatment of Skin Diseases the danger of absorption is even greater than in the dressing of wounds, as the absorbing surface is often very much more extensive, and in addition the more irritant antiseptics are obviously not admissible here. In many cases of successful treat- ment with bodies of the aromatic series, the remedy seems to act not only as an antiseptic but also as a rnild irritant and astringent. Pyrogallol is believed by some dermatologists to be of value only from its reduc- ing action depriving the superficial tissues of their oxygen. 4. The antiseptics have been frequently employed for their Disin- fectant Action on the Bowel, and as far as the putrefaction of the in- testinal contents is concerned, with success. The disintegration of the food by microbes in the bowel may be estimated by the amount of double sulphates appearing in the urine, and in several series of exper- iments these have been found to be notably diminished by bodies of the aromatic series. Fewer microbes have been found in the faeces 390 ORGANIC DRUGS ACTING AFTER ABSORPTION. also after these antiseptics have been administered. When, however, bacterial infection of the wall of the bowel is treated with these anti- septics, the results are less favorable. In typhoid fever, in which the subject has been most frequently examined, the number of the typhoid bacilli in the stools has not been lessened to any noticeable extent, and the majority of clinical observers seem to be very sceptical as to any relief of the symptoms being attained or of the duration of the dis- ease being shortened by their use. Any drug used for the disinfection of the intestine must not be irri- tant, nor very poisonous. It must not be too soluble, since otherwise it may be absorbed from the stomach and fail to reach the bowel, and on the other hand it must be soluble to some extent, or it cannot mix very intimately with the contents of the intestine. Carbolic acid is scarcely fitted for this purpose, for it irritates the stomach and is also rapidly absorbed. Some of the cresols have been recommended of late years, and the naphtalin preparations have also enjoyed some repu- tation. Salol and its congeners have the advantages of being almost completely insoluble and harmless in the stomach and of being dis- solved and rendered active by the intestinal juices, and have been found of value in excessive putrefaction of the contents of the bowel. It has to be added that putrefaction in the bowel is best treated by its evacuation by a purgative, such as one of the mercurial preparations, which also have a high antiseptic value. 5. The antiseptics of the benzol series are excreted in great part by the kidneys, and the urine is thus rendered weakly antiseptic and irritant. This fact has been taken advantage of in the treatment of Septic Diseases of the Bladder and Urethra ; the drugs used for this pur- pose must not be too irritant to the gastric mucous membranes, and must be easily absorbed, and not dangerously poisonous. Here, again, salol has been found of value as well as salicylic acid. The forms in which the benzol derivatives are excreted by the kidney are generally much less irritant and antiseptic than that in which they are adminis- tered. In estimating the value of each as a urinary disinfectant, it must also be remembered that many of them are liable to undergo oxidation in the urine itself. (See also copaiba series and urotropin.) 6. Small quantities of some of the more volatile members of this series, especially of the hydrocarbons, escape by the lungs, and this has led to their use in Pulmonary Disease, especially in phthisis. It may be stated at once that careful observers are almost all united in the belief that the internal administration of these remedies has practically no antiseptic effect on the microbes in the lungs. Some relief is often ob- tained, but, it is believed, only through their disinfectant action in the stomach and bowel. Antiseptic remedies have also been inhaled in vapor or spray and have been injected into the trachea and even into the lung directly, but as far as the tubercle bacillus is concerned, they have had no result in the hands of the vast majority of physicians. In cases of gangrene of the lung, foetid bronchitis, etc., the inhalations re- lieve the patient to some extent, and certainly lessen the offensive odor. ANTISEPTICS OF THE AROMATIC SERIES. 391 7. The use of antiseptics to Destroy Pathogenic Germs in the Tissues after Absorption is very limited. It is now recognized to be hopeless to attempt to find a single body which will destroy all forms of bacteria in the tissues, while leaving the host uninjured, but there is still reason to believe that in the future specific antiseptics may be found for at least some of the constitutional diseases. Such a specific action is seen in the effects of quinine on the organism of malaria, of salicylic acid in rheumatic fever, and of mercury in syphilis, all of these ap- parently acting more strongly on the cause of the disease than on the tissues of the patient. While it may be hoped that the antiseptic treatment of internal maladies has not reached its final limit, the only constitutional disease in which the aromatic series has been shown to be of incontestable value is acute rheumatism, and in many other conditions which were formerly treated with benzol antiseptics, they have proved rather injurious than otherwise. Renewed interest has been aroused in this question recently by the proposal to treat septic- aemia by the intravenous injections of antiseptics, but investigation has shown that even the least dangerous cause symptoms of poisoning in much smaller quantities than would be necessary to render the blood an antiseptic solution. There is reason to believe that solutions containing several of the benzol series are more strongly antiseptic than those containing an equal percentage of the individual pure bodies, and that the mixture of such a body as carbolic acid with an antiseptic of another kind, e. g., mercuric perchloride, is still more efficient than the correspond- ing proportion of either alone. This appears to be due to a change in the solubility of the disinfectant, at any rate in some cases. If a poison is to penetrate into the interior of an organism in quantity it must be as soluble in the protoplasm as in the fluid in which it is ap- plied, for it is obvious that it will not leave a medium in which it is readily soluble for one in which it is dissolved with difficulty. Ac- cordingly it is found that fats and oils in which the members of the aromatic series are very soluble are not suitable as media for their ap- plication, for the poisons remain in the oily menstruum and fail to penetrate the microbes in which they are less soluble. On the other hand, the addition of inorganic salts to an aqueous solution of carbolic acid often increases its antiseptic power, because the poison becomes less soluble in the water and shows a greater tendency to escape from it into the interior of the microbes. Fate in the Tissues. The fate of the members of the aromatic series in the body is very uniform in one respect the benzol ring is rup- tured only with great difficulty. In the great majority of cases the changes which these substances undergo in the tissues affect only the hydrogen or the side chains attached to the carbon atoms, and leave the form in which these last are attached to each other unchanged. The chief exceptions to this rule are pyrogallol and gallic acid, which seem to undergo more or less complete oxidation to carbonic acid and water. Some oxidation takes place in the aromatic series, however, the simpler forms, such as benzol and aniline, tending to form hydroxyl 392 ORGANIC DRUGS ACTING AFTER ABSORPTION. compounds, while those with a side chain formed of methane deriva- tives tend to oxidize it to carboxyl. The oxidation of the benzol com- pounds in the tissues therefore results in the formation of oxybenzols and aromatic acids, and this oxidation is probably not limited to any one particular tissue or organ. These bodies are not, however, ex- creted in this form in ordinary cases, but enter into secondary combi- nations in which they appear in the urine. The hydroxyl bodies unite with sulphuric and glycuronic acids to form double sulphates (ether-sulphuric acid salts) and glycuronates, while the aromatic acids are excreted in combinations with glycocoll, which are known as hip- puric, salicyluric, etc., acids. The last synthesis probably occurs chiefly in the kidney, while the double sulphates are said to be formed in the liver. A few examples of the changes undergone in the tissues may elu- cidate the above statement. Benzol (C 6 H 6 ) is oxidized to phenol (C 6 H 5 OH), and to dioxybenzols lC 6 H 4 <^ H ) , which combine in the kidney with sulphuric and glycuronic acids to form phenol-sulphuric (C 6 H 5 O SO 3 H) and phenol-glycuronic acids, and the correspond- ing dioxybenzol compounds. Toluol (C 6 H 5 CH 3 ) is oxidized to benzoic acid (C 6 H 5 COOH), which combines with the glycocoll of the body to form hippuric acid (C 6 H 5 CO NHCH 2 COOH). Xylol V I is oxidized only in one side chain and forms toluic acid , which is excreted in combination with glycocoll as toluric acid. Although a general resemblance exists in the oxidation products of these bodies in the tissues and in the forms in which they are excreted, considerable differences are noted in the details. Thus, naphtalin undergoes the same oxidation as benzol, forming naphtol in place of phenol, but while the phenol appears in the urine in combination with sulphuric acid almost entirely, the naphtol combines with glycuronic acid for the most part. BIBLIOGRAPHY . Consult that given under the individual members CABBOLIC ACID, SALICYCLIC ACID, etc. Antiseptic Action. Dougall. Med. Times and Gazette, 1872, i., p. 495. Bucholtz. Arch. f. exp. Path. u. Pharm., iv., p. 1. Gerhardt. Ergebnisse der Physiol., iii., 1., p. 153. Fortescue-Brickdale. Lancet, 1903, i., p. 98. Mieczkowski. Mit. a. d. Grengebiet, ix., p. 405. Koch. Mittheilung aus dem Kaiserlich. Gesundheitsamt., i., p. 234. Jalan de la Croix. Arch. f. exp. Path. u. Pharm., xiii., p. 175. Cash. Keports of British Local Government Board, 1886. Stemberg. Bull, of National Board of Health, 1881. Schulz. Pfluger's Arch., xlii., p. 517. Biernacki. Ibid., xlix., p. 112. Kronicj u. Paul. Ztschr. f. Hygiene, xxv., p. 1. Spiro u. Bruns. Arch. f. exp. Path. u. Pharm., xli., p. 353. ANTISEPTICS OF THE AROMATIC SERIES. 393 General Action. Brunton and Cash. Proc. Roy. Soc., xlii., p. 240. Schuttzenu. Graebe. Arch, t Anat. u. Phys., 1867, p. 166. Schultzen u. Naunyn, Ibid. , p. 349. Nencki. Ibid., p. 399, 1870. Baumann. Pfliiger's Arch., xiii., p. 285. Baumann u. Preusse. Arch. f. Anat. u. Phys., 1879, p. 245. Baumann and pupils. Zts. f. phys. Chem., i.-vii. Bokorny. Pfliiger's Arch., Ixiv., p. 306. Nencki u. Giacosa. Zts. f. physiol. Chem., iv., p. 325. Nencki. Arch. f. exp. Path. u. Pharm., i., p. 420; xxx., p. 300. Karpow. Arch, des Sciences biolog., ii., p. 305. fiaglioni. Ztschr. f. allg. Phys., iv., p. 313. Steiff. Zts. f. klin. Med., xvi., p. 311. Binet. Trav. de Labor, de Therap. exp. de Geneve, ii., p. 143. Schmiedeberg. Arch. f. exp. Path. u. Pharm., xiv., p. 379. 1. Carbolic Acid. Carbolic acid or phenol, the first of the modern antiseptics to be in- troduced, acts like the rest of the simpler benzol compounds as a General Protoplasm Poison, although in the vertebrates it acts more powerfully on the central nervous system than on the other tissues. Its poisonous effects are well seen when it is applied to unicel- lular organisms such as the protozoa. Even dilute solutions cause immediate arrest of all movements ; the organism assumes a spherical shape and loses its transparency, and, unless the solution be very attenuated, dies in the course of a few minutes. Plant cells are acted on in the same way, and the individual cells of more highly organized animals, such as the ciliated epithelium of the air passages and the spermatozoa, are killed at once when brought in contact with carbolic acid. There is some evidence, however, that very dilute solutions of carbolic acid, as of other antiseptics, tend to increase the activity of protoplasm. Thus Biernacki and Schulz have found that while solu- tions of phenol, such as are used as surgical antiseptics, are immediately fatal to the yeast plant, very dilute solutions increase its activity. The effect of carbolic acid on protoplasm has, however, been studied chiefly in the bacteria. Its antiseptic power, while always considerable, is found to vary greatly with the species of microbe. Thus, while it is fairly poisonous to the ordinary pyogenic organisms, it has to be present in very concentrated form to destroy the more resistant spores of an- thrax, and like other antiseptics, is much less poisonous to the microbes than to the protozoa and other simple forms of life. The development and reproduction of many microorganisms has been found to be much delayed, or altogether prevented, as long as they remained in a solution of one part of carbolic acid in 400600 parts water, but in order to kill the spores very much more concentrated solutions (5 per cent.) were required, and Koch found that the spores of the anthrax bacilli were destroyed by 5 per cent, carbolic solution only after they had remained in it for two days. It seems to vary considerably in its action on the unorganized fer- ments ; thus it is said not to retard appreciably the fermentations 394 ORGANIC DRUGS ACTING AFTER ABSORPTION. produced by emulsin, diastase and my rosin, even when present in the solution up to 5 per cent., while pepsin, ptyalin and the rennet fer- ment are weakened by somewhat smaller quantities. Carbolic acid precipitates Proteids in solution and also in the cells. It does not seem to enter into any such firm combination with them as is formed when tannic acid or a salt of one of the heavy metals is added to a solution of proteid, for it can be washed out of the precipitate with comparative ease. Its action in precipitating albumins may rather be compared to that of alcohol, in which the proteid is precipi- tated, not because an insoluble compound is formed, but because of a change in the nature of the solvent. It results from this that carbolic acid penetrates more thoroughly than the metallic antiseptics, which are rendered insoluble by the albumin they meet, and whose action therefore tends to remain confined to the surface. This coagulation of the proteids occurs whenever carbolic acid is brought in contact with the tissues. On the Skin a white, opaque scar is formed by concentrated phenol, which becomes red and shining af- terwards and then falls off in a few days, leaving a light brown stain which may remain for several weeks. Even a five per cent, solution applied to the fingers produces tingling and warmth, which is often fol- lowed by opacity and shrinking of the epidermis and a sense of numb- ness. This numbness may amount to almost complete anaesthesia if more concentrated solutions are applied, no pain being felt even when the skin is cut through. When applied for some time and prevented from evaporating, carbolic acid may cause extensive dry gangrene of the part from its penetrating through the surface layer and reaching the deeper tissues. Applied to a Wound in five per cent, solution, phenol induces pain and irritation and the formation of a white pellicle of coagulated proteids. It causes irritation and necrosis of the Mucous Membranes, and if applied in sufficient quantity may lead to sloughing and acute inflammation. This local effect may prove fatal from shock and collapse when large quantities of the undiluted acid are swallowed, the eifect resembling exactly that produced by other corrosive sub- stances. Apart from its local action, carbolic acid has important effects after its absorption into the blood. The most marked of these are the changes in the Central Nervous System. When a small quantity of carbolic acid is injected into the frog, the first symptoms, apart from those produced by the pain of the injection, consist in an unusual quiet and in the absence of the spontaneous movements. Later, quivering of individual muscles, and apparently of the individual bundles of muscle fibres, sets in, and this is soon accompanied by an increase in the reflex irritability and eventually by convulsions similar to those seen after strychnine. These movements gradually become weaker, and eventually complete paralysis is induced, while the heart continues to beat and the muscles and nerves react to the electric shock. A dilute solution of carbolic acid applied directly to the exposed spinal cord paralyzes the sensory elements immediately, while leaving ANTISEPTICS OF THE AROMATIC SERIES. 395 unaffected the motor fibres and the cells of the anterior horn (Bag- lioni). In mammals, a very similar set of symptoms are produced, save that there is often no noticeable preliminary stage of depression. Some weakness and lethargy may be present, however, and are followed by marked muscular tremor, which resembles the shivering produced by cold. At intervals this is interrupted by sudden twitches in different muscles, and later by clonic convulsions. The respiration and the pulse are at first accelerated, but afterwards are slow, irregular, and weak. The movements become feeble and appear at longer intervals, the respiration is shallow and irregular, and the animal passes into a condition of collapse, in which, however, the sensibility to pain is often preserved. Eventually death occurs from asphyxia. After very large doses the collapse may be immediate, no convulsions being observed, the heart and respiration often ceasing simultaneously. In most cases salivation is a marked symptom, and the temperature often falls far below the normal. In man, convulsions are comparatively rarely seen. When large quantities are taken, immediate unconsciousness may result and death follow within a few minutes. How far this is due to the local cor- rosion, and how far the direct action on the central nervous system is involved, cannot be determined. In more gradual poisoning, de- pression and weakness, headache, nausea and vomiting are followed by giddiness, noises in the ears, pallor and collapse, with irregular pulse and respiration, and cold perspiration ; fainting and unconsciousness then lead to failure of the breathing, and death. Delirium and excite- ment have been observed in some cases. Fatal poisoning may arise from swallowing the concentrated or dilute solution, or from absorption from wounds and abscesses. It has also occurred in man from absorp- tion through the unbroken skin. The autopsy sometimes gives no special indications of the cause of death, save the local corrosion of the alimentary canal. Inflammation and necrosis of the intestine is said to have been observed in some cases in which the poison was absorbed from skin wounds, and fatty degeneration is sometimes induced in the liver and the renal epithelium, but is not constant. The convulsions in the frog arise from an increase in the irritability of the spinal cord, especially of the cells of the anterior horn (Baglioni), for they are not arrested by section of the medulla oblongata. In mammals the sudden contractions of isolated muscles appear due to a similar action on the spinal cord, but the clonic convulsions and the persistent tremors are probably of cerebral origin, and Berkholz found the cerebral cortex abnormally irritable after carbolic acid. The rarity of convulsions in man has not been satisfactorily explained. In some cases the course of the intoxication is too short, the large amount of poison swallowed inducing immediate collapse, while in others their absence may be due to the debility of the patient from disease ; but in a considerable number of cases of poisoning in which neither of 396 ORGANIC DRUGS ACTING AFTER ABSORPTION. these conditions was present, no convulsions were observed. A sim- ilar contrast between the effects of a poison on the lower animals and on man has been mentioned already under morphine. In all cases, the primary stimulation of the central nervous system is followed by depression and paralysis if large doses are administered. The acceleration of the Respiration and of the Heart seen in mam- mals has been supposed to be an indirect result of the increased mus- cular movement and convulsions, but this seems to be incorrect, for the heart is found to be accelerated before the convulsive movements and tremor appear, and the frog's heart is accelerated in cases where no movements whatever occur. It would seem probable that the acceleration of the heart is due to direct action on the muscle or on the regulating nerves. The subsequent slowing is undoubtedly due to muscular action. The acceleration of the respiration precedes the increased move- ment also, and would therefore seem to be due to action on the med- ullary centre, which is first stimulated and later paralyzed. The vaso-motor centre is said by Gies to be depressed at once by the injec- tion of carbolic acid into the blood, but it may be questioned whether it too is not first excited when the poison is absorbed more slowly. It is undoubtedly depressed in the later stages of poisoning, and this, together with the weakness and slowness of the heart, causes a fall in the blood-pressure. The peripheral Nerves and Muscles do not seem to be affected in general poisoning in mammals, although in the frog their irritability and the capacity for work of the muscle may be somewhat reduced. On the direct application of solutions of carbolic acid to the nerves or muscles, these are at once killed, like other forms of living matter. The increased Secretion of saliva, perspiration and tears which is seen in poisoning in mammals is probably of central origin, and may possibly be associated with the nausea and vomiting. The fall in Temperature in carbolic acid poisoning seems, for the main part, to be due to the collapse, although it is impossible to state how far this may be aided by some alteration of the regulating func- tion, such as is seen in the closely related group of the antipyretics. Carbolic acid added to the defibrinated Blood leads to the slow forma- tion of methsemoglobin, but this does not occur in the living animal. Occasionally some destruction of the red blood cells is caused in animals through the injection of carbolic acid directly into the blood vessels, and in one case of poisoning in man haemoglobin was detected in the urine, indicating that some of the red cells of the blood had been destroyed. Excretion. Carbolic acid passes through the tissues unoxidized for the most part, but a certain proportion of it undergoes a partial oxida- tion to hydroquinone and pyrocatechin. These combine in the body with sulphuric and glycuronic acids, and are excreted in the urine as double sulphates (ether sulphates) and glycuronates of phenol, hydro- quinone and pyrocatechin. The two last-named bodies are somewhat ANTISEPTICS OF THE AROMATIC SERIES. 397 unstable, and tend to undergo further oxidation, through which colored substances are formed. When carbolic acid has been absorbed, there- fore, the urine tends to assume a dark, dusky-green color which may change to brown or even black. This change may occur in the body, and the urine is very often passed of a greenish-brown color, but further oxidation takes place on exposure to the air, resulting in deeper colora- tion which commences at the surface of the fluid and gradually extends downwards. The depth of the shade depends not on the amount of phenol sulphate in the urine, but on that of the dioxybenzols, and a darker urine is often observed, therefore, when the absorption has oc- curred from an open wound (in which the conditions are especially favorable to oxidation) than from much larger quantities absorbed from the alimentary canal. The presence of glycuronates in the urine may lead to its reducing Fehling's solution, and thus give rise to the suspicion of glycosuria. On the other hand, the passage of these bodies through the kidney often causes some irritation and albumin uria. The double sulphates of the urine are, of course, much increased, and in the dog the whole of the ordinary inorganic sulphates may disappear, the urine contain- ing only double sulphates. The Chlorphenols, in which chlorine is substituted for one or more of the hydrogen atoms of carbolic acid, are much more poisonous to microorgan- isms than the original substance, but are also somewhat more poisonous to mammals, so that they have not been much used. A similar intensifying effect is seen in the chlorine substitution products of the narcotic series, e. g. , chloroform. The most poisonous of the monochlor-phenols is parachlorphenol. Bromol or tribromphenol has been used to a limited extent in therapeutics as a disinfectant and caustic. PREPARATIONS. ACIDTJM CARBOLICUM (B. P.), PHENOL (U. S. P.), carbolic acid or phenol (C 6 H 5 OH) forms colorless, deliquescent crystals when recently prepared, but often assumes a reddish tinge from oxidation. It ha.s a characteristic odor and is intensely corrosive. It is soluble in about 15 parts of water, but becomes liquid when 10 parts of water are added to 90 of the crystals, forming the Acidum Carbolicum Liquefactum (B. P.), Phenol Liquefactum (U. S. P.). This must be carefully distinguished from the ordinary solution of carbolic acid, which contains only about 5 per cent, of phenol, while the liquefied carbolic acid con- tains about 90 per cent. Carbolic acid, 0.03-0.2 G. (J-3 grs.). Liquefied carbolic acid, 1-3 mins. Glyceritum Phenolis(\J. S. P.), Glycerinum Acidi Carbolici (R. P.), 20 per cent, of carbolic acid in glycerin. Unguentum Phenolis, U. S. P., 5 per cent.; Unguentum Acidi Carbolici, B. P., 4 per cent. Trochiscus Acidi Carbolici (B. P.), each containing 1 gr. Suppositoria Acidi Carbolici (B. P.), each containing 1 gr. Therapeutic Uses. Carbolic acid is used as an antiseptic in surgical operations in 2-5 per cent, solution in water. It now plays a muck less important role in surgery than it did in the first days of anti- sepsis ; in fact, in many clinics in which it was once the only anti- septic used, and in which it was applied in all the manifold prepara- 398 ORGANIC DRUGS ACTING AFTER ABSORPTION. tions then known, carbolic acid is now employed only to preserve the instruments from infection. This change is no doubt partially due to apprehension of its irritant action, and to the occasional cases of pois- oning which occurred from its use, but chiefly to the alterations in surgical technique which have been introduced since the antiseptic method was first invented. The tendency now is to reduce the use of antiseptics to a minimum and to trust instead to stricter cleanliness and asepsis. Its irritant action and the danger of absorption have also rendered it unpopular as a dressing or lotion after operations or injuries, where there is any large absorbent surface, or where irritation is liable to be injurious, as in most forms of skin disease. It is still used as a disinfectant in septic wounds, though greater reliance is now placed on corrosive sublimate and the oxidizing germi- cides, such as hydrogen peroxide. Strong carbolic acid has been applied to disinfect wounds, its poisonous effects being avoided by im- mediately washing it off with alcohol. Harrington has recently drawn attention to the danger of applying dilute solutions in bandages to injured fingers and hands ; he found records of over a hundred cases in which this had led to gangrene necessitating amputation. Carbolic acid has also been employed as a caustic, the liquefied preparation being preferred for this purpose. It is less painful than other caustics owing to its anaesthetizing action, but it is also less efficient. Its local action on the sensory nerve terminations has been utilized in itching skin diseases and it may be noted that some recent local ansesthetics are benzol derivatives (see page 314). The treatment of deep-seated abscesses and inflammation by the local injection of carbolic acid solutions has passed into desuetude, and a similar fate has befallen its use to limit the extension of erysipelas. The spray of carbolic acid has been advised in laryngeal and pulmonary disease, but is scarcely met with in recent years. A solution of carbolic acid has been employed as an irritant to cause inflammatory reaction, cicatricial adhesion and consequent obliteration of small cysts, such as hydrocele, and in nsevus. Internally carbolic acid was tried as an intestinal disinfectant, and in many infectious fevers. It causes marked irritation of the stomach, however, and probably little of it reaches the bowel, as it is rapidly absorbed, and other less irritant and less soluble bodies have therefore been substituted for it. Its use as a remedy in constitutional diseases is entirely obsolete. It may be prescribed as a pill or in capsules for internal use, as the solutions are more liable to cause irritation ; only the pure acid is prescribed either for internal or external application. Crude carbolic acid may be employed to disinfect stools, latrines, etc., and is quite unsuited for therapeutic use. The ointment is comparatively seldom prescribed, as it is found more irritant than many other equally power- ful antiseptics. The glycerite may be used as a very weak caustic. ANTISEPTICS OF THE AROMATIC SERIES. 399 Solutions of carbolic acid in oil have little or no antiseptic action, because they fail to penetrate into the microbes. Poisoning. In carbolic acid poisoning, when it has been taken by the mouth, the first treatment is the removal of the poison by the stomach tube, and the administration of demulcents such as white of egg ; when absorption has occurred from the skin or from a wound, the dressing should be removed at once. Lime suspended in syrup has been recommended in cases in which the acid has been swallowed, in the hope that an insoluble combination may be formed in the stom- ach. The combination of phenol with sulphuric acid in the tissues forms a comparatively harmless body, and Baumann and Preusse there- fore suggested the administration of sodium sulphate in large quanti- ties. It is found, however, that this is of little or no use, either because the tissues in which the synthesis occurs are entirely paralyzed by the excess of phenol, or more probably because the phenol does not combine with sulphates as such in the body, but with organic sulphur com- pounds which are only in process of being oxidized to sulphuric acid. When coma and collapse set in, the patient is to be sustained by the application of warmth externally, and by the administration of such central nervous stimulants as caffeine, atropine, or camphor ; artificial respiration may eventually be used, although there is little prospect of resuscitation if the intoxication has advanced so far. The corrosion induced by carbolic acid locally may be treated by washing the part with alcohol, which dissolves the acid readily. Alcohol has also been used in cases in which the poison has been swallowed, and the results are said to have been satisfactory. The alcohol only serves to dilute the poison and does not form any combination with it, so that it would seem advisable to remove the mixture by the stomach tube. BIBLIOGRAPHY. Hmemann. Deutsche Klinik, 1870, 1871. Arch. f. exp. Path. u. Pharm., iv., p. 280. Gies. Ibid., xii., p. 401. Baumann and his pupils. Pfliiger' s Arch. , xiii. , p. 285. Zts. f. phys. Chem., i., p. 244 ; ii., pp. 273, 350; iii., pp. 156, 177. Arch. f. Anat. u. Phys., 1879, p. 245. Bill Amer. Jour, of Med. Sci., Ixiv., p. 17. Salkowsky. Pfliiger' s Arch., v., p. 335. Hoppe-Seylor. Ibid., v., p. 470. Plugge. Ibid., v., p. 538. Prudden. Am. Jour, of Med. Sci., Ixxxi., p. 82. Tauber. Arch. f. exp. Path. u. Pharm., xxxvi., p. 197. Schmiedeberg. Ibid., xiv., p. 288. Turtschaninow. Ibid., xxxiv., p. 208. Berkholz. See Unverrickt, Centralb. f. inn. Med., 1895, p. 4. Baglioni. Arch. f. [Anat. u.] Phys., 1900, Supplem., p. 193. Ztschr. f. allg. Physiol., iii., p. 313. Minervini. Arch. f. klin. Chirurg., lx., p. 687. Harrington. Am. Jour, of Med. Sci., cxx., p. 1. Cresol. The three cresols are nearly related to carbolic acid chemically, and re- semble it very closely in their effects. Metacresol is less poisonous to mam- mals and less irritant, and at the same time seems to be more destructive tr microbes than carbolic acid. Orthocresol is more dangerous than carboli acid, and paracresol is the most powerful poison of all. The symptoi 400 ORGANIC DRUGS ACTING AFTER ABSORPTION. produced by these bodies are identical with those of phenol. They are ex- creted as cresol double sulphates mainly, but some appears in the urine as the sulphate of a more highly oxidized form, dioxytoluol. The cresols are constituents of the tars and other crude antiseptic substances. They are only slightly soluble in water, and there has been some difficulty in render- ing them available for surgical use, but this has been overcome by forming emulsions (creoliri), or by dissolving them with the aid of salts (solveol, sol- utol) or suspending them by means of soap (lysol). These are not claimed to be pure preparations of cresol, but the three isomeric cresols have recently been introduced as tricresol, which dissolves in water to the extent of 2 J per cent. These preparations are not devoid of poisonous properties, as is often stated by interested individuals, but they are not so dangerous as carbolic acid. They are used chiefly as surgical antiseptics, but creolin has also been given as an intestinal disinfectant, although with indifferent results. Their value as surgical antiseptics has been denied by some writers and there is no question that it has been much overrated by others. Kresamine (ethylendi- amine and tricresol) is said to be more strongly antiseptic than tricresol, and has been recommended in diseases of the skin as an ointment or solution. Cresol (U. S. P.), a mixture of the three cresols, forms a colorless or straw- colored fluid with a phenol odor. Soluble in 60 parts of water. Dose, 0.05 c.c. (1 min.). Liquor Cresolis Compositus (U. S. P.), Cresol 50 percent, suspended in water by means of soap, is used in a diluted form as a surgical disinfectant. BIBLIOGRAPHY. Seybold. Ztschr. f. Hygiene, xxix., p. 377. Thymol. Another phenol homologue is thymol, which resembles carbolic acid closely in its action, though it causes less central nervous stimulation. Con- vulsions and tremors are rarely induced in either frogs or mammals, and when present, are very much less intense than those following carbolic acid. The animal generally sinks into a condition of apathy and weakness, which gradually passes into collapse and death. Thymol is less soluble in the fluids of the body, and is therefore absorbed more slowly than carbolic acid. It is also less irritant to wounded surfaces and is, according to most observ- ers, considerably more poisonous to putrefactive organisms, while less pois- onous to the higher animals. In poisoning from its use, fatty degeneration of the liver, marked congestion and even consolidation of the lungs, and ir- ritation of the intestines have been observed. It is excreted in the urine in combination with sulphuric and glycuronic acids, partly unchanged, partly oxidized to thymolhydroquinone. There is also found in the urine a green coloring substance, which becomes blue on the addition of acid, and which seems nearly related to, but not identical with indigo. Thymol is said to be more liable to cause renal irritation than carbolic acid and albumin and even blood have been repeatedly observed in the urine after its absorption. Thymol (U. S. P., B. P.) (C 6 H 3 C 3 H 7 CH 3 OH) occurs in common thyme and several other plants, and forms large, colorless crystals, which have the odor of thyme and are very insoluble in water. 0.03-2G. (-30 grs.) in pills, capsules, emulsion, or in solution in dilute alcohol. Thymol has been used occasionally as an antiseptic lotion in ^ per cent, solu- tion and as a mouth-wash and gargle, for which carbolic acid is rendered un- suitable by its unpleasant odor and its corrosive action. As an internal remedy it has proved a failure in the treatment of various constitutional diseases, such as acute rheumatism, phthisis and typhoid fever. It has recently been highly recommended as an anthelmintic for uncinaria or anchylostoma ; it is given in capsules or emulsion in large doses, 2 G. (30 grs.), repeated in two hours, and followed in six or eight hours by a brisk saline purge. ANTISEPTICS OF THE AROMATIC SERIES. 401 BIBLIOGRAPHY. Husemann. Arch. f. exp. Path. u. Pharm., iv., p. 280. Blum. Zts. f. physiol. Chem., xvi., p. 514. Deutsche med. Woch., 1891, p. 186. Leuin. Virchow's Arch., Ixv., p. 164. Baelz. Arch, der Heilkunde, xviii., p. 60. Kuessner. Habilitationschr., Halle, 1878. Eucalyptol. Eucalyptol (C 10 H 18 O) is the chief constituent of oil of eucalyptus, which is obtained from Eucalyptus globulus and some other species. It is also contained in the oil of cajuput and in other volatile oils. It has been re- commended as a surgical antiseptic and in the same class of internal diseases as thymol, but does not seem to have any special virtues distinguishing it from the general class of volatile oils. Eucalyptol (U. S. P.), a colorless fluid, having a characteristic, camphor- aceous odor and a pungent, spicy, cooling taste. It is almost insoluble in water, but is miscible with alcohol in all proportions. Resorcin. The three dioxy benzols resorcin, pyrocatechin and hydroquinone re- semble carbolic acid in their effects, but produce a more intense stimu- lation of the central nervous system, for convulsions have been observed in man after their use. This is especially true for the two last, resorcin being much less toxic than these. Resorcin seems to be equally or more strongly antiseptic than phenol, and is somewhat less poisonous, while the others are more dangerous ; it is less irritant and caustic than carbolic acid. All three dioxybenzols are excreted in the urine in combination with sulphuric and glycuronic acids. They are in part subjected to further oxidation, leading to coloration of the urine similar to that seen in carbolic acid poisoning. Pyro- catechin and hydroquinone when added to blood form metha3moglobin much more readily than phenol, and also tend to form it in the body when the intoxication does not progress too rapidly to allow of this alteration in the living animal. They cause a much greater destruction of the red blood cells than phenol. Resorcinol (U. S. P.), resorcin, metadioxybenzol (C 6 H 4 (OH) 2 ), colorless, very soluble crystals, with a faint aromatic odor. 0.3-0.6 G. (5-10 grs.) ; 3 G. (45 grs.) in 24 hours. Resorcin is a remedy which has fallen into almost complete disuse. At first introduced as an antiseptic, it was prescribed for a short time as an antipyretic, but has proved as unsuitable for this purpose as carbolic acid or aniline, which reduce fever temperature, but cause symptoms of collapse very readily. It has been used as an intestinal antiseptic and in rheumatic fever, but has here again been supplanted by less dangerous remedies. As an ex- ternal application, it* has been applied in ointment (5-10 per cent.) in skin diseases, and has been injected in cystitis and gonorrhoea in solution (1-3 per cent.) but in both cases is liable to produce irritation and pain. As an internal remedy it should be prescribed in dilute solution (1-2 per cent.). BIBLIOGRAPHY. Andeer. Centralbl. f. d. med. Wis., 1881-1889. Baumann. Zts. f. phys. Chem., i., p. 244. (See Carbolic Acid.) Brieger. Zts. f. klin. Med., iii., p. 25. Arch. f. Anat. u. Phys., 1879, Suppl., p. 61. Martin. Therap. Gaz., 1887, p. 289. Surbeck. Deutsch. Arch. f. klin. Med., xxxii., p. 515. Danilewsky. Arch. f. exp. Path. u. Pharm., xxxv., p. 105. 26 402 ORGANIC DRUGS ACTING AFTER ABSORPTION. 2. Pyrogallol. Pyrogallol, the only trioxybenzol that has been largely used, pro- duces nervous symptoms resembling those of carbolic acid, when given in very large doses to animals, In the cases of poisoning which have been observed in man, the symptoms closely resembled those caused by smaller quantities in animals, in that these nervous phenom- ena were almost entirely absent, and the poison acted not so much directly on the central nervous system, as upon the blood corpus- cles. Many of the other members of this series cause some destruc- tion of the red cells, but none of them approach pyrogallol in the inten- sity of their eifects. The red blood cells become shrunken and angular and lose most of their haemoglobin, which escapes into the plasma and is changed into methsemoglobin ; the blood therefore assumes a brown- ish-red color, which may be detected in the living animal by the dis- coloration of the skin and mucous membranes. If the intoxication is not too acute, icterus follows, and haemoglobin and methsemoglobin are excreted in the urine. In the blood, fragments of red cells and " shadows," or red cells deprived of their coloring matter, are seen in large numbers, and the spectrum of methsemoglobin can be obtained easily. The kidneys are also affected, and the resulting nephritis is indicated by the presence in the urine of albumin, epithelium, and casts, along with the products of the decomposition of the blood. The nephritis may lead to uraemic convulsions, which are sometimes accompanied by the nervous tremors characteristic of this series, and also by dyspnoea and cyanosis from the lack of haemoglo- bin in the blood. The formation of methaemoglobin is generally be- lieved to be connected with the well-known reducing properties of py- rogallol, but whether the methaemoglobin is a direct result of the reduction caused in the haemoglobin, or whether a secondary oxidation accompanies this action, is unknown. Pyrogallol is excreted in part in combination with sulphuric acid in the urine, in part as unknown oxidized products, which give the urine a dark brown or black color, even when no blood pigments are contained in it. In fatal poisoning death seems to be due to the blood changes, and the consequent ne- phritis and jaundice, rather than to the direct effect of the drug on the central nervous system. It has been stated that the debris of the red blood cells fails to pass through the capillaries and thus leads to thrombosis, but this has been denied by later investigators. The skin is dyed brown when pyrogallol is applied to it, from the products of oxidation formed. Pyrogallol (U. S. P.), pyrogallic acid (C 6 H ? (OH) 3 ), light, colorless crystals or laminae when freshly prepared, which rapidly assume a darker color on exposure to light and air. It is very soluble in water and reduces the salts of the heavy metals even in the cold. It is used only externally. Pyrogallol is used in the treatment of several forms of skin disease, especially in psoriasis, in which it is applied in ointment (5-20 per ANTISEPTICS OF THE AROMATIC SERIES. 403 cent.). It is dangerous to apply it to very large surfaces, however, and many authorities therefore advise the use of chrysarobin in its stead. Pyrogallol ought never to be used internally. Its curative action in skin diseases may be due to its slight irritant and antiseptic properties, but is referred by some to its reducing action. Gallaceto- phenone (CH 3 CO C 6 H 2 (OH) 3 ) has been recommended as a substi- tute for pyrogallol in skin affections. BIBLIOGRAPHY. Wedl Wiener Sitzungsber., Ixiv., p. 405. Neisser. Zts. f. klin. Med., i., p. 88. Weyl u. Anrep. Arch. f. Anat. u. Phys., 1880, p. 234. Rekowski. Therap. Monatsch., 1891, p. 487. (Gallacetophenone. ) 3. Naphtalin and Naphtol (Naphthol). Naphtalin and its compounds alpha- and beta-naphtol differ in some respects from the other members of the series. They are all insoluble in water, but the naphtols are dissolved in the alkalies. Some ques- tion has arisen as to whether Naphtalin is really an antiseptic in itself, or whether it owes its activity to the formation of the more soluble naphtols. Animals poisoned with it do not exhibit the ordi- nary symptoms of poisoning with an aromatic body, even when it is administered for several weeks, but suffer from diarrhoea and lose flesh rapidly, either from disturbance of the alimentary canal or from renal disorder. The urine soon contains albumin, casts and epithelium, and the kidney is found in a condition of parenchymatous nephritis. The changes in the eye caused by naphlalin and naphtol have excited some interest. The retina is seen with the ophthalmoscope to be dotted over with numerous bright points, or sometimes to contain large yellow plaques, and after large doses subretinal effusion has been observed. At the same time, atrophy of the optic nerve may occur, and bright points are seen in the vitreous humor similar to those in the retina. A slight cloudiness appears in the lens and increases rapidly until it becomes quite opaque and resembles an ordinary cataract in man. This does not seem to be secondary to the retinal changes, but is the result of an inflammatory infiltration beginning in the ciliary body and iris and extending into the lens and finally into the posterior surface of the cornea. These changes in the eye have generally been observed in animals treated with large doses of naphtaline or naphtol, and have not occurred in such intensity in man ; but v. d. Hoeve states that com- mencing retinal degeneration may be induced in man by the use of naphtol internally or externally and cautions against its prolonged ad- ministration. Large doses of the Naphtols induce symptoms similar to those of carbolic acid poisoning, except that in the dog no convulsions have been observed, and in the other mammals they seem less pronounced. They are irritating to the mucous membranes when they come in con- 404 ORGANIC DRUGS ACTING AFTER ABSORPTION. tact with them in solution or in vapor ; thus they cause sneezing and coughing when applied to the respiratory passages, and in the course of excretion induce pain in the bladder and urethra with strangury and swelling of the mucous membrane. Injected subcutaneously or ab- sorbed from the alimentary canal in animals, they induce acute nephritis with the appearance of albumin and haemoglobin in the urine, and some nephritis has been caused in man from their external application. They seem to have less effect on the circulation and respiration than the other aromatic antiseptics, but resemble them in tending to destroy the red cells of the blood. Alpha-naphtol has been found to be more strongly antiseptic than the beta compound, and may be more poison- ous, as is generally stated, but no satisfactory investigation has appeared regarding this point. Beta-naphtol is several times as strongly ger- micidal as carbolic acid, and is the form used in therapeutics. Naphtalin is partly oxidized in the tissues and appears in the urine as alpha- and beta-naphtol and naphtoquinone, all in combination with glycuronic and sulphuric acid. The naphtols are excreted in combi- nation with glycuronic acid mainly. These bodies and their oxidized products give the urine a reddish-brown tint, which may become deeper on exposure to the air, but in some cases it retains its ordinary color. PREPARATIONS. Naphthalenum (U. S. P.), naphtalin or naphtalene (C 10 H 8 ), colorless, insol- uble crystals with a coal-tar odor and a hot, aromatic taste. 0.06-0.3 G. (1-5 grs.). BETANAPHTHOL (U. S. P.), NAPHTHOL (B. P.), Beta-naphtol (C 10 H 7 OH), white or yellowish-white, insoluble crystals or powder, with a faint phenol odor and a hot taste. 0. 2-0. 6 G. (3-10 grs. ). Therapeutic Uses. Naphtalin and naphtol were at first introduced as external applications in parasitic skin diseases of various forms, but have been more extensively prescribed as intestinal disinfectants. In some disorders, such as diarrhoea, in which the walls of the intestine are only secondarily affected by the putrefaction of the contents, they have proved very efficacious, but when the intestinal walls themselves are the seat of the primary disease, as in typhoid fever and dysentery, they are of more doubtful value. They have been employed as an- thelmintics to a limited extent, and apparently with some success, though they have not proved so reliable as some of the older drugs used for this purpose. Naphtol is more largely used than naphtalin in internal medication, and may be prescribed as a powder or in capsules. They are used externally as ointments (5-10 per cent.). Naphtalene and naphtol ought to be avoided in irritation of the kidneys, bladder or urethra. BIBLIOGRAPHY. Willenz. Therap. Monatsheft, 1888, p. 20. Baatz. Centralbl. f. inn. Med., 1894, p. 857. Lesnik. Arch. f. exp. Path. u. Pharm., xxiv., p. 168. ANTISEPTICS OF THE AROMATIC SERIES. 405 Magnus. Therap. Monats., 1887, p. 387. Klingmann. Virchow's Arch., cxlix., p. 12. Manca and Ovio. Arch. Ital. de Biologic, xxxiv., p. 265. v. d. Hoeve. Arch. f. Ophthalmol., liii., p. 74. 4. Tar. The action of the various crude preparations of the antiseptic series resembles that of the pure principles but as in most of them the creo- sols, guaiacols and other less poisonous aromatic compounds are present in larger quantity than the phenols and dioxybenzols, they are less poisonous than carbolic acid and its simpler homologues. At the same time these higher combinations do not seem to be much less antiseptic than the simpler benzol derivatives, so that several of the crude prepa- rations possess considerable value in surgery and medicine. PREPARATIONS. Fix Liquida (U. S. P., B. P.), tar, is obtained from the wood of Pinus palustris and other species of Pinus by destructive distillation and contains a very large number of aromatic bodies mixed with others of less importance. Oleum Picis Liquids (U. S. P.), oil of tar, is a volatile oil distilled from tar, and is similar to creosote, except that it consists almost entirely of guaiacols and their compounds. 0.05-0.3 c.c. (1-5 mins.). Syrupus Picis Liquids (U. S. P.), syrup of tar, 4-12 c.c. (1-3 fl. drs.). Unguentum Picis Liquidse (U. S. P., B. P.). Pix Carbonis Pr separata (B. P.), prepared coal-tar. Liquor Picis Carbonis (B. P.), a solution of coal-tar in tincture of Quil- laia bark. Oleum Cadinum (U. S. P., B. P.), oil of cade or empyreumatic oil of juniper. Juniper tar oil is the tar distilled from the juniper, and contains dioxybenzol and guaiacol combinations. It is less strongly disinfectant than the other tars. Tar is a valuable disinfectant, which is very generally available and is much cheaper than the purer bodies of the aromatic series. It may be used for the disinfection of excrementa, latrines, etc., where the cost of even crude carbolic acid would be prohibitive. Tar has also been used with considerable success as an antiseptic in skin- diseases, in which it may be applied either alone or as an oint- ment. It is only slightly irritating to the skin, and some absorption occurs, as is often seen by the dark color of the urine. Internally it has been used occasionally as an anthelmintic and intestinal disinfec- tant, much more frequently as an " expectorant " in cough mixtures. Whether it has any eifects on the lungs or not in these cases may be questioned. It is generally given as the syrup, sometimes as tar water. BIBLIOGRAPHY. Nencki u. Sieber. Arch. f. exp. Path. u. Pharm., xxxiii., p. 1. Strom. Arch. d. Pharmacie, ccxxxvii., p. 525. 406 ORGANIC DRUGS ACTING AFTER ABSORPTION. Creosote. Creosote may be regarded as a wood-tar from which the more poisonous phenols and the less volatile bodies have been eliminated, leaving guaiacols and creosols as the chief constituents. Its action is similar to that of carbolic acid, except that it has less tendency to induce nervous symptoms, and is less irritant and poisonous. On the other hand, it seems at least as strongly antiseptic as carbolic acid, and according to some investigators, far excels it as a germicide. PREPARATIONS. Creosotum (U. S. P., B. P.) is obtained from wood-tar, preferably from beech tar, and is an almost colorless oily liquid with a smoky odor and hot, burning acrid taste. It is slightly soluble in water, but mixes readily with alcohol. It tends to darken in color when exposed to the light. 0.05-0.3 c.c. (1-5 mins.). Aqua Creosoti (U. S. P.), a very dilute solution of creosote in water, less than one per cent. 2-8 c.c. (J-2 fl. drs.). Mistura Creosoti (B. P.) containing spirits of juniper, -1 fl. oz. Unguentum Creosoti (B. P.). Creosote may be administered in pills, capsules, in solution in alcohol or cod-liver oil, or as a mixture (B. P.). The wine of creosote, which has been a popular remedy, contains it dissolved in wine along with some brandy and tincture of gentian. It ought not be allowed to reach the mucous membranes in a concentrated form, as it is liable to irritate them. Therapeutic Uses. Creosote is comparatively seldom used except in the treatment of pulmonary phthisis and gangrene, and chronic bronchial inflammation. It is generally given by the mouth in these cases, but has also been injected hypodermically or into the rectum ; the vapor is recommended as an inhalation, and some practitioners have injected creosote solution into the trachea, in order to ensure its reach- ing the lungs. None of these methods are believed to give such good results as the ordinary administration by the mouth. The results of creosote medication are still disputed. Many clin- icians state that a general improvement follows it in phthisical pa= tients, that the appetite is improved, the cough and expectoration les- sened, and that the patient feels stronger and better. On the other hand, others are extremely sceptical as to any benefits arising from creosote, and regard it as merely one of the countless remedies which have been recommended in this condition, and which after a shorter or longer period of popularity have passed into oblivion. It is generally supposed by the advocates of the creosote treatment that the remedy destroys the tubercle bacillus in the lungs through its antiseptic properties. On the other hand, animals infected with tubercle and treated with creosote die as soon as controls which are untreated, and the sputum of phthisical patients treated with creosote is as viru- lent as that of others not so treated. Besides, the administration of creosote by other ways than by the mouth is said to be very much less efficacious. Another explanation of the creosote action is that it acts ANTISEPTICS OF THE AROMATIC SERIES. 407 as an intestinal antiseptic and prevents the secondary infection of the bowel ; but it has been objected to this that the other intestinal anti- septics are of little value in tuberculosis. It seems useless to specu- late on the method of action until it has been definitely determined that creosote is of value in phthisis, and this can be done only by careful statistical inquiry. The medical profession seems to have much less faith in the efficacy of the creosote treatment than it had a few years ago, when it was not generally recognized that pulmonary tuber- culosis is curable by hygienic measures in a considerable proportion of instances. Creosol, an ether of dioxytoluol, is contained in creosote and other wood- tar, and has, as far as is known, effects similar to those of the allied bodies, but has not been investigated so carefully as some of the others. Guaiacol, the methyl ether of pyrocatechin, seems to be somewhat more poisonous than carbolic acid according to Marfori, whose preparations, however, were by no means pure ; the symptoms induced were those character- istic of the series. It is excreted in the urine in combination with sulphuric and glycuronic acids. Guaiacol Carbonate seems to have the same effects as guaiacol, into which it is decomposed in the intestine. It was found a few years ago that guaiacol applied to the skin over a sufficiently wide area produced a marked fall of temperature in fever, but this does not seem to be any specific effect of guaiacol, and would probably have resulted from the application of any other equally volatile member of the group. The explanation is that a certain proportion of the guaiacol applied is absorbed from the skin, and the fall of temperature is one of the symptoms of poisoning. Considerable quantities of guaiacol have been recovered from the urine after this method of medication. The fall of temperature is generally abrupt and is accompanied by some exhaustion and weakness, and by profuse perspiration. The temperature soon rises again to its former height with shivering and rigors, and there seems good reason, therefore, why guaiacol should not be classed iimong the more satis- factory antipyretics. Guaiacol (U. S. P.), (C 6 H 4 - OH- OCH 3 ), colorless crystals, or fluid with an agreeable aromatic odor, soluble in 53 parts of water and in alcohol. Dose, 0.5 c.c. (8 mins.). Guaiacol has been administered as a substitute for creosote in tubercular disease. It is generally given in solution in alcohol or cod-liver oil, or in pills. It has been injected hypodermically. Guaiacolis Carbonas (U. S. P.) ((C 7 H 7 O) 2 CO 3 ), an almost tasteless powder, is given in cachets in doses of 0.2-0.5 G. (3-8 grs. ) in pulmonary phthisis. Ichthyol. Ichthyol, thiol, and similar bodies possess some antiseptic action, although they are believed to be less powerful than carbolic acid. Applied to the skin, ichthyol causes slight irritation, which is apparently of benefit in some cu- taneous diseases, and it has therefore been used extensively for this action. It is said to cause marked contraction of the vessels when it is applied locally, but this requires confirmation. A certain amount of absorption oc- curs when it is rubbed into the skin, for the sulphur of the urine has been found to be augmented. Taken internally in large quantities, it acts as a gastric and intestinal irritant and produces diarrhoea, but it is only very feebly poisonous. It has been said to lessen to a marked extent the nitro- genous metabolism, but this seems incorrect, for Helmers found only a very 408 ORGANIC DRUGS ACTING AFTER ABSORPTION. slight and inconstant fall in the nitrogen of the urine in man. It is ex- creted in the urine and probably by the intestinal wall. Ichthyol has been strongly recommended in the treatment of a number of skin diseases, including erysipelas. It is generally used as an ointment con- taining equal parts of ichthyol and of vaseline, but may be used in ten per cent, or even weaker dilution. It has also been advised as an applica- tion over inflamed and rheumatic joints, indurated glands and swellings, and chronic inflammations of the pelvic viscera, and is said to cause the absorp- tion of the products of inflammation. Its effects can be explained in these cases only by the slight irritant action on the skin. It has been given internally in pills or capsules in doses of 0.2-0.5 G. (3-8 grs.) in cases of rheumatism, erysipelas, and in many chronic diseases, but seems of very doubtful benefit. In fact, ichthyol has in the last few years been enthusiastically praised as a remedy in the most diverse conditions, and it seems probable that its sphere of utility will be very much more restricted in the future, if it does not disappear from therapeutics entirely. BIBLIOGRAPHY. R. Abel Centralbl. f. Bacteriologie, xiv., p. 413. Zuelzer. Monatsh. f. prakt. Dermatologie, 1886, p. 547. Helmers. Virchow's Arch., cxxxv., p. 135. 5. Salicylic Acid. Salicylic acid differs from phenol chiefly in being very much less poisonous to the higher animals, while it is practically of equal an- tiseptic value, provided the conditions are favorable. The salicylates produce the same effects as the free acid, excepting that they are much less irritant to the skin and mucous membranes. It was for- merly stated that the salicylate of soda, which is the only salt that has been largely used, was devoid of antiseptic action, but this has been shown to be incorrect. Antiseptic Action. Salicylic acid retards the digestion of proteids by the gastric and pancreatic juices, and the decomposition of gluco- sides by the unorganized ferments, but how far this effect is due to the free acid, and how far to a specific antiferment-action, cannot be defi- nitely stated. The putrefaction of proteid solutions, and the alcoholic and acetic acid fermentations are also retarded, or entirely prevented by the presence of comparatively small quantities of salicylic acid or of the salicylates. They offer some points of contrast with carbolic acid, however, for it is found that if much proteid be present the salicylic preparations are generally less efficient than phenol ; this is perhaps due to the phenol being volatile and therefore penetrating more readily and forming less stable combinations with the proteid. Salicylic acid on the other hand does not evaporate, and therefore preserves bodies which are exposed to the air for a longer time than carbolic acid, which is soon dissipated. These considerations may perhaps explain the very different results which have been obtained by different ob- servers in regard to the comparative germicidal power of these sub- stances. The movements of plant protoplasm, protozoa and leucocytes are prevented by salicylic acid as by quinine and the other aromatic antiseptics. ANTISEPTICS OF THE AROMATIC SERIES. 409 Irritant Action. Salicylic acid is much less irritant than phenol, but when it is applied for some time as a powder to wounds, mucous membranes, or even the skin, it may induce the same corrosion and necrosis as have been . mentioned under carbolic acid. In solution it has a destructive action on the horny layer of the epidermis, which be- comes softened and easily removed, without any noticeable irritation having been induced. It sometimes causes soreness and irritation of the mouth and throat when swallowed in powder, and congestion and even erosion of the mucous membrane of the stomach have been ob- served. In dilute solution, however, the acid has no such effect, and even comparatively concentrated solutions of the salts seem almost devoid of corrosive properties. Symptoms. Salicylic acid and its salts are rapidly absorbed from the stomach and intestine, and as a general rule produce no symptoms, unless when given in very large doses. Some individuals, however, are peculiarly sensitive to the action of salicylic acid, and in these, comparatively small doses are followed by symptoms which are gen- erally of only slight importance, but which are sometimes sufficiently grave to cause anxiety, and in very rare cases, have been followed by death. The ordinary symptoms are a feeling of heaviness and fulness in the head, with hissing or roaring sounds in the ears exactly resembling those produced by quinine. These may be followed by some confusion and dulness, and by indistinct sight and hearing. Very often the patient complains of excessive perspiration and a sense of warmth all over the body. Dyspnoea, marked by exceedingly deep and labored respiration, has been noted in more serious cases of poisoning, and a condition of collapse with slow weak pulse, subnormal temperature, and partial or complete unconsciousness may follow. In others, de- lirium and hallucinations of sight and hearing have occurred, these being more frequently seen in chronic alcoholic patients .and in cases of diabetes than under other conditions. Albumin, casts, and even haemoglobin and blood in the urine have been noted as sequelae. Vari- ous forms of skin eruptions have been described as occurring under the use of salicylic acid, sometimes after a single dose, but much more frequently after prolonged treatment. They resemble those seen under the antipyretics, but seem to be less frequently elicited by salicylic acid. Abortion has been repeatedly observed under salicylate treat- ment, but, as in the case of quinine, it seems open to question whether this was due to the remedy or to the disease. Haemorrhages from the uterus, nose, mouth and intestine have also been credited to the action of this drug, and, in fact, nose-bleeding has been said to occur in a considerable proportion of the cases treated with it. Numerous other symptoms have been noted after salicylic acid, but so rarely that a doubt may be entertained as to whether they were not due to some special condition, or perhaps to some impurity in the drug. In animals, salicylic acid injected intravenously causes some acceler- ation of the pulse and respiration, followed by slowness and weakness 410 ORGANIC DRUGS ACTING AFTER ABSORPTION. of the heart, and often by marked dyspnoea. Depression of the central nervous system is shown by slowness, weakness and incoordination of the spontaneous movements, and eventually by stupor and arrest of the respiration, which is generally preceded by convulsions. Photo- phobia and clonic spasms have been observed in some dogs. Hyper- semia of the kidney, liver, brain and tympanum are sometimes found at the autopsy on dogs poisoned with salicylic acid, and when the drug has been given in powder, congestion, irritation and necrosis of the gastric mucous membrane. This irritation of the stomach often causes vomiting in dogs, and the poison being thus eliminated, no further symptoms appear. In the frog, salicylic acid produces quickened respiration and in- creased reflexes, followed by depression of the spontaneous movements, tremor and clonic contractions. The heart is slow, dilated and weak. The symptoms elicited by salicylic acid and its salts are therefore verv indefinite, and with few exceptions occur so seldom in man that they may be discussed very shortly. The Disorders of Hearing have been ascribed to congestion of the tympanum, but may perhaps indicate some changes in the nerve cells of the ear analogous to those observed under quinine. As a general rule they pass off in the course of a few hours or days, but they some- times leave a more or less permanent impairment of the sense of hear- ing. The Dimness of Sight, sometimes amounting to complete blind- ness, is due to vascular or retinal changes in the eye (see Quinine), and some disturbance of the circulation of the brain and head may be the cause of the dulness and fulness of the head complained of, and of the not infrequent epistaxis. Maragliano showed by plethysmographic measurements that the Vessels of the Skin are dilated by salicylic acid in the same way as by the antipyretics. The exact mechanism by which these alterations in the distribution of the blood are produced is unknown, but the most probable explanation would seem to be that the vaso-dilator centres in the medulla controlling these areas are excited. The general Blood-Pressure is found to be increased by small quan- tities of the salicylates from stimulation of the vaso-con stricter centre, while after very large injections into the blood vessels, the pressure is lowered, partly perhaps from depression of the centre, but mainly from the cardiac action of the drug. Small quantities are found to accelerate the Heart in animals in the same way as small doses of the other aromatic bodies, apparently from direct action on the cardiac muscle. Very large doses produce a slow, weak, and dilated heart, and a corresponding fall in the blood-pressure. The acceleration of the Respiration and the dyspnoea, which have been noted occasionally in man, seem to be due to some central action. In animals the respiration is first accelerated to some extent, and then slowed, and some observers have attributed the acceleration to irrita- tion of the endings of the pneumogastric nerves in the lungs, without, however, bringing forward any satisfactory evidence in support of this explanation. It is more probable that the respiratory centre is first ANTISEPTICS OF THE AROMATIC SERIES. 411 excited and then depressed, and eventually paralyzed by very large quantities of the drug. Death seems to be due to this paralysis, the heart continuing to beat for some time afterwards. The effects of salicylic acid on the Central Nervous System seem to be comparatively slight, except in cases in which a special idiosyncrasy exists. No such convulsive action as occurs under others of the aro- matic series has been observed under it, and in animals there seems no marked depression save in the medulla oblongata. The convulsions which are observed before death, are probably not due to the direct action of the drug, but to the asphyxia. In the medulla oblongata the respiratory and vaso-constrictor centres, and probably the vaso-dilator, seem to be first stimulated and then depressed. In the frog depres- sion and paralysis of the spinal cord are produced by large doses. The Perspiration which so often follows the administration of sali- cylic preparations, may be due in part to the dilation of the skin ves- sels, but is probably to be ascribed rather to increased activity of the sweat centres. Some of the Skin Rashes may also be caused by the dilation of the cutaneous vessels, and perhaps in all cases this may be looked upon as a favorable condition, which leads to eruptions in indi- viduals who are predisposed to them. The peripheral Muscles and Nerves do not seem to be more affected by salicylic acid than by the other members of the series. Salicylic acid and its salts increase to some extent the Secretion of the Urine, probably through a direct action on the renal epithelium, although the increased formation of urea may also play a part in the slight diuresis. Irritation of the kidney and nephritis are observed in some cases, with the appearance of albumin and blood in the urine. The salicylic preparations produce a slightly augmented flow of Bile, apparently from some specific action on the liver cells. The increase is so small, however, that some doubt is expressed by most writers on the subject. Pfaff found that in one case of biliary fistula in man the concentration of the bile was also increased, the solids being augmented in greater proportion than the fluid. Salicylates have been said to lower the normal Temperature, but this seems to be erroneous, except when very large quantities produce a condition akin to collapse. Some of the results may also be due to the use of impure preparations. In fever patients, however, it often causes a marked fall of temperature, and it was formerly used as an antipyretic for this reason. The action is probably explained by the dilation of the cutaneous vessels and the increase in the output of heat. (See Antipyretics.) Dilation of the skin vessels also occurs in normal persons after salicylates, but this is probably counterbalanced in them by increased heat formation. The fall in temperature after salicylic acid is generally less in extent and of shorter duration, than that fol- lowing the members of the antipyrine series. . In its passage through the tissues, salicylic acid modifies the Meta- bolism, as is shown by an increase of 1012 per cent, in the nitrogen and sulphur of the urine. This indicates a considerably augmented 412 ORGANIC DRUGS ACTING AFTER ABSORPTION, decomposition of the proteids of the body, but whether it is accom- panied by increased oxidation is unknown. A still more notable augmentation of the uric acid excreted has been observed, different authors estimating it at 3045 and even 100 per cent. The number of leucocytes in the blood has been found to undergo a corresponding increase. The form in which salicylic acid circulates in the blood was for- merly the subject of some discussion, owing to the erroneous belief that its salts were devoid of antiseptic action. It is now known to exist in the blood as the salicylates of the alkalies. Gaglio states that it is taken up from the blood by the synovial membranes and rapidly ex- creted into the cavities of the joints, and is thus capable of exercising a specific action in acute rheumatism. It is Excreted by the kidneys, for the most part in a combination with glycocoll, which is known as salicyluric acid, and which is strictly analogous to hippuric acid. Some of the salicylic acid is excreted uncombined. It has also been found in the milk, perspiration and bile, but does not appear to be ex- creted into the stomach. Several compounds which owe their virtues to the salicylic acid radicle are used in medicine, and all produce similar results after ab- sorption, but vary in their local action. Methyl Salicylic Ester, which occurs in many plants and forms some 90 per cent, of the oil of winter- green, and almost the whole of the volatile oil of birch, has a hot, burning taste, and like other volatile oils produces a feeling of warmth in the stomach. In many cases it is well borne, but some patients complain of pain in the stomach, loss of appetite and even nausea and vomiting. It is rapidly absorbed and produces the characteristic symptoms of salicylic acid in large doses, roaring sounds in the ears and more or less deafness. It is partly excreted as salicyluric acid, the decomposition probably occurring mainly in the intestine. Salol, the phenyl salicylic ester, is a very insoluble, crystalline body, which has little or no local action in the mouth or stomach, but is de- composed in the intestine by the fat-splitting ferment of the pancreatic juice. Some decomposition also appears to occur in the stomach, at any rate under certain conditions. The products of its decomposition, salicylic and carbolic acids, are absorbed and produce their usual effects. Salol is used chiefly as a substitute for salicylic acid, but the formation of phenol from it in the body must not be overlooked, for in several cases of dangerous poisoning which have been observed under it, the symptoms were those characteristic of carbolic acid, and the urine became dark in color from the phenol oxidation products. In moderate quantities, salol produces the disturbances of hearing observed under salicylic acid, without any symptoms of carbolic poisoning. Other salicylic acid compounds, similar to salol, are betol or naphtalol (the beta-naphtol salicylate), cresalol (cresol and salicylic acid), thymo- salol (from thymol), guaiacohalol, while saliphen, malakine, etc., have been mentioned among the antipyretics. They are less poisonous than salol, and may be used for most purposes as substitutes for salicylic ANTISEPTICS OF THE AROMATIC SERIES. 413 acid. Saliphen, malakine and their allies have a more powerful anti- pyretic action than salicylic acid. On the other hand, the salicylic esters, including methyl and phenyl salicylates, are less antiseptic than salicylic acid and its salts. Salicin, a glucoside found in many species of willow and poplar, is decomposed into salicylic alcohol, which is oxidized to salicylic acid in the body, so that its action after absorption is similar to that of the acid. It is unknown whether the decomposition occurs in the alimen- tary canal or in the tissues, but from the fact that it is excreted mainly as salicin when it is injected intravenously, it would seem probable that the decomposition, like that of the ordinary esters, takes place chiefly in the intestine. It is very bitter, but does not irritate the mucous membranes, and is not so certain in its action as salicylic acid and some of its esters. When administered by the mouth it is excreted in the urine partly as salicin, partly as saligenin or salicyl alcohol, and partly as salicylic and salicyluric acids. PREPARATIONS. ACIDUM SALICYLICUM (U. S. P., B. P.), salicylic acid (C fi H 4 OHCOOH) small, white, needle-like crystals, or a light crystalline powder, odorless with a sweetish, afterwards acrid, burning taste, slightly soluble in water, very soluble in alcohol or ether. A reddish tinge indicates the presence of car- bolic acid or other impurities, and salicylic acid for internal use ought to be entirely colorless. 1 Salicylic acid is much more soluble in solutions of neu- tral salts, such as the borates or citrates, than in pure water. 0.3-2 G. (5-80 grs.). It is generally given in capsules or tablets. Unguentum Acidi Salicylici (B. P.), 2 per cent. SODII SALICYLAS (U. S. P., B. P.), sodium salicylate (C 6 H 4 OHCOONa), a white odorless powder with a sweetish taste, very soluble in water, less so in alcohol. 0.6-2 G. (10-30 grs.) in capsules or tablets, or dissolved in syrup. Lithii Salicylas (U. S. P.), 0.3-2 G. (5-30 grs.). Ammonii Salicylas (U. S. P.), 0.25 G. (4 grs.). Strontii Salicylas (U. S. P.), 1.0 G. (15 grs.). Oleum Gaultherice, (U. S. P.), oil of wintergreen, a colorless or yellowish fluid with a characteristic, pleasant odor and a sweetish, aromatic taste, insoluble in water, soluble in alcohol, contains 90 per cent, of methyl salicylate. 0.3-1 c.c. (5-15 mins. ) in emulsion or capsules. Oleum Betulce (U. S. P.), oil of sweet birch. Methylis Salicylas (U. S. P.), artificial oil of wintergreen (C 6 H 4 OHCOOCH 3 ), is practically identical with the oil of sweet birch and forms 90 per cent, of the oil of wintergreen. It may be prescribed in the same doses and forms as the latter. Spiritus Gauftherise (IT. S. P.) is used as a flavor chiefly. 1 c.c. (15 mins.). Salicinum (U. S. P., B. P.), salicin (C 6 H n O 5 OC 6 H 4 CH 2 OH), a glucoside obtained from several species of willow and poplar, consists of white, silky, crystalline needles, with a very bitter taste, soluble in 28 parts of water. It is decomposed by ferments into glucose and saligenin or salicyl alcohol (C 6 H 4 OHCH 2 OH). 0.5-2 G. (8-30 grs.) or more every 3 or 4 hours, given in powder, capsules or in solution, which, however, is very bitter. 1 Salicylic acid formed synthetically from phenol is often said to be more poisonous than that obtained from the oil of wintergreen (methyl salicylate), but this is due not to any difference in the acid, but to the presence of carbolic acid and other impurities in the artificial preparation. 414 ORGANIC DRUGS ACTING AFTER ABSORPTION. SALOL (B. P.), PHENYLIS SALICYLAS (U. S. P.), phenyl salicylate (C 6 H 4 - OHCOOC 6 H 5 ), a white crystalline powder, odorless or faintly aromatic, almost tasteless, almost insoluble in water, decomposed by the pancreatic juice into salicylic acid and phenol. 0.5-2 G. (5-30 grs.) in powder or capsule. Aspirin or acetylsalicylic acid, is very slightly soluble in water and has a more pleasant acid taste than salicylic acid but offers no further advantages over it. It is decomposed into salicylic acid in the intestine. Dose, 2-3 G. (30-40 grs.). Therapeutic Uses, Salicylic acid and the salicylate of soda were at one time used to a considerable extent as antiseptics in surgery, and in- deed promised to supplant carbolic acid for this purpose, as they were less irritating and also less poisonous. They have been less used of late years, and although bacteriological experiment has shown that the acid is at least as destructive to the pyogenic organisms as carbolic acid, most surgeons find it less satisfactory in practice. 1 Salicylic acid is occasionally applied locally in excessive sweating, and has also been used in various skin affections in which it is desir- able to soften or partially dissolve the epidermis. Both acids and salts are absorbed too rapidly to act as intestinal disinfectants. In 1875 it was found to have antipyretic properties, and for a few years it was used as a general antipyretic in fever, but has been entirely supplanted for this purpose by the more recently discovered antipyrine series. It was also suggested as a substitute for quinine, but has no such specific action on the malarial organisms. The chief sphere of usefulness of salicylic acid at the present time is in the treatment of acute rheumatic fever, in which it seems to have a specific action only excelled by that of quinine in malaria. Other members of the aromatic series have some effect in this condition, but none of them equal the salicylic preparations in efficacy. Under this treatment the pain and swelling in the joints rapidly lessen, the tem- perature often falls, and the course of the disease is shortened. It is still debated whether the salicylic treatment reduces the liability to endocarditis and pericarditis, which are common complications of acute rheumatic fever ; some clinicians even state that it increases the risk of these complications, while others advise the discontinuance of the treatment when any symptoms arise from the heart. The view more generally entertained, however, is that the cardiac affections are less often met with and are less severe under salicylic treatment, and very often it is continued in small quantities even after the heart is undoubt- edly involved in the disease. The remedy sometimes fails in rheuma- tism, as quinine does in malaria, and it sometimes acts more satisfac- torily in one joint than in another. Large doses (1-2 G. or 15-30 grs.) repeated every 2-3 hours are necessary in some cases at first, the quantity being reduced as the symptoms abate. Salicylic acid is less frequently used than the salicylate of soda or salol, but some clinicians 'Salicylic acid has been used very largely as a preservative in wine and beer. No evil effects have been definitely shown to follow the prolonged use of liquors thus treated, but it is not impossible that they may be injurious, and several governments have found it advisable to prohibit its use for this purpose. ANTISEPTICS OF THE AROMATIC SERIES. 415 hold that the acid is the most efficient of the three. Oil of winter- green may also be used here, but, like salicylic acid, is more liable to cause gastric irritation. When high fever is present the antipyretic combinations of salicylic acid, such as malakine, may be used with advantage. Salicin is less disturbing to the stomach than the other preparations, but is less certain in its effects and has to be given in larger quantities. Salicylic acid has also been used in the various forms of disease which are roughly classified as rheumatic chronic rheumatism, arth- ritis, neuralgia, myalgia but the effects are less satisfactory than in acute rheumatism. The lithium salt is contained in the U. S. P. because lithium is erroneously credited with a special solvent action on the uric acid in these diseases. In other acute constitutional diseases accompanied by fever, salicylic acid is of less value than in acute rheumatism so that it would appear that it has a specific action on the unknown cause of this malady. Salicylic acid in some cases promotes the absorption of effusions into the serous membranes, such as the pleura, and also subretinal effusion. It is unknown how this is effected, but it scarcely seems probable that the slight diuretic action of the drug is sufficient to account for it. The cholagogue action of the salicylates is quite inconsiderable in comparison with that of the bile itself, and in any case in which an increase of the bile secretion is desirable, recourse should be had rather to the latter. It has recently been suggested by Kuhn that the salic- ylic salts excreted in the bile may retard the growth of microbes and thus prove of value in the treatment of liver and gall-bladder infections. The solubility of the salicylates and their rapid absorption precludes their use as intestinal antiseptics, but salol has been used to lessen putrefaction in the bowel, and even to act upon the bacilli of typhoid fever and of tubercle infecting the intestinal wall. Kumagawa, how- ever, states that the putrefaction in the bowel as measured by the in- dican in the urine is unchanged by its administration, and he found enormous numbers of bacteria in the fa3ces afterwards. It certainly seems of little value in typhoid fever or in tuberculosis of the intes- tine. Intestinal calculi have been formed in a few instances from prolonged treatment with salol, which failed to be decomposed in the intestine and formed masses of considerable size. Salol was at one time supposed to be absorbed only after its de- composition in the intestine by the pancreatic juice, and Ewald there- fore suggested its use as a means of diagnosing stenosis of the pylorus. He supposed that in cases in which the food was delayed or prevented from passing into the intestine, the reaction of salicylic acid in the urine would appear correspondingly late or be entirely absent. But some salol seems to be absorbed from the stomach, and, on the other hand, the interval between its administration and the appearance of the salicylic reaction in the urine is so variable in normal individuals that the test is of little value. Salol has been used to coat pills and prevent their solution in the stomach. presums Methyl salicylate, or oil of wintergreen, is muscular and articular rheumatism, it beiil quantities thus reach the focus of disease thai by the mouth. Absorption certainly occurs| proved by the appearance of salicyluric acid tion of the skin is liable to be excited, and is doubtful in these diseases. 1 BIBLIOGRAPHY. Kolbe. Journ. f. pract. Chemie, x., p. 89 ; xi., p. 9 ; Quincke. Berl. klin. Woch., 1882, p. 709. Charted and McLennan. Brit. Med. Journ., 1889, ii. Bauer u. Kiinstle. Deutsch. Arch. f. klin. Med., xxr Sassetzky. Virchow's Arch., xciv., p. 485. Huber. Deutsch. Arch. f. klin. Med., xli., p. 129. Maragliano. Zts. f. klin. Med., xvii., p. 291, and xiv. Gottlieb. Arch. f. exp. Path., xxvi., p. 436. Baumann. Zts. f. phys. Chem., i., p. 253. Binz. Arch. f. exp. Path. u. Pharm., vii., p. 280, Luthje. Deutsch. Arch. f. klin. Med., Ixxiv., p. 163. Kleineberger and Oxenius. Ibid., Ixxx., p. 225. Kuhn. Mtinchener Med. Woch., 1904, p. 1457. Nencki. Arch. f. exp. Path. u. Pharm., xxxvi., p. 40] Bochefontaine. Comptes rendus d. 1. Soc. de Biol., de 1' Academic, Ixxxv., p. 574; Ixxxvii., p. 657. Mosso. Arch. f. exp. Path. u. Pharm., xxvi., p. 267. C. Virchow. Zts. f. physiol. Chem., vi., p. 78. Buss. Deutsch. Arch. f. klin. Med., xv., p. 457. Baelz. Arch. d. Heilkunde, xviii., p. 60. Pfaff. Jour, of Exp. Med., ii., p. 49. Gaglio. Arch. Ital. de Biol., xxxi., p. 304. Schreiber u. Zandy. Deutsch. Arch. f. klin. Med., Ixii., p. 242. Goodbody. Journ. of Physiol., xxv., p. 399. Ulrici. Arch. f. exp. Path. u. Pharm., xlvi., p. 321. Salol. Nencki. Arch. f. exp. Path. u. Pharm., xx., p. 367. Lesnik. Ibid., xxiv., p. 167. 1 Mesotan, or methoxymethylsalicylate, has been introduced as a substitute for oil of wintergreen in external treatment, but has no advantages of any consequence over the older drug. ANTISEPTICS OF THE AROMATIC SERIES. 417 Hesselbach. Practitioner, xlv., p. 12. Sahli. Therap. Monats., 1887, p. 333. EwaJd u. Sievers. Ibid., p. 289. Marshall Brit. Med. Journ., 1897, ii., p. 78. Salicin. Marme. Gottingen. Nachricht., 1878, p. 229. Maclagan. Lancet, 1876, i., p. 342. Senator. Berl. klin. Woch., 1877, p. 181. Aspirin. Dreser. Pfliiger's Archiv, Ixxvi., p. 306. Singer.. Ibid., Ixxxiv., p. 527. Gazert. Deutsch. Arch. f. klin. Med., Ixviii., p. 142. Other Aromatic Oxy- acids. The two isomers of salicylic acid, meta- and para-oxybenzoic acid, are said to be almost devoid of antiseptic properties, and, although some doubt may be entertained as to the correctness of this statement, they have never been used in medicine except experimentally. The cresotinic acids resemble salicylic acid in their effects, and the para- cresotinate of soda has been used occasionally as an antipyretic and substi- tute for salicylic acid. The metacresotinate is very much less active, while the orthocresotinate possesses a dangerous action on the heart. The para- cresotinate is somewhat less poisonous than salicylic acid. The cresotonic acids are found as impurities in some commercial specimens of salicylic acid, but these ought not to be used for internal administration, as the presence of the orthocresotonic acid may affect the heart. The alpha- and beta-oxynaphtoic acids are possessed of antiseptic proper- ties, which are said to be somewhat greater than those of carbolic and sali- cylic acids, but they are less soluble in water, while the sodium salt is less antiseptic. The acids are irritant and produce diarrhoea and symptoms similar to those of salicylic acid. They seem to be at least as poisonous as carbolic acid, and have been used as external antiseptics only to a very limited extent. BIBLIOGRAPHY. Suss. Berl. klin. Woch., 1876, p. 445. Demme. Therap. Monats., 1890, p. 191. ffenne. Inaug. Diss., Bern, 1890. Charteris. Brit. Med. Journ., 1891, i., p. 695. Ellenberger u. Hofmeister. Arch. f. exp. Path. u. Pharm., xxiv., p. 261. Wittenz. Therap. Monatsheft, 1888, p. 20. Sulphocarbolates. The sulphon group lessens the toxicity in the same way as carboxyl, and the sulphocarbolates or para-phenol-sulphonates are therefore less poisonous than carbolic acid. The sulphocarbolates of sodium and zinc have been used as external antiseptics, and the sulphocarbolate of sodium has been adminis- tered to arrest fermentation in the stomach. The zinc salt possesses some astringent action and has been used with good results as an injection in gon- orrhoea. The sodium salt is probably excreted in the urine unchanged. Aseptol or sozolic acid is a 33 per cent, solution of orthophenol-sulphonic acid in water but very often contains some of the para-acid. Sodii Sulphocarbolas (B. P.), Sodii Phenolsulphonas (U. S. P.), or sodium para- phenol-sulphonate (C 6 H 4 OHSO 2 ONa,2H 2 O), forms colorless, transparent prisms, without odor, and with a saline taste. Soluble in 5 parts of water. 0. 3-1 G. (5-15 grs.). Zinci Sulphocarbolas (B. P.) (Zn(OHC 6 H 4 SO 3 ) 2 H 2 O) forms colorless, trans- parent, efflorescent crystals, which are very soluble in water and in alcohol 27 418 ORGANIC DRUGS ACTING AFTER ABSORPTION, BIBLIOGRAPHY. Serrant. Comptes rendus de PAcadem., c.. pp. 1465 and 1544. Hueppe. Berl. klin. Woch., 1886, p. 609. Samter. Inaug. Diss., Berlin, 1887. Benzole Acid. Benzoic acid possesses almost the same action as salicylic acid in the body, and like it, is poisonous only in comparatively large quanti- ties. It seems to be equally, or according to some observers, more strongly antiseptic, and like salicylic acid irritates the mucous mem- branes, while its salts are practically devoid of this last property. Benzoic acid is, however, apparently less stimulant to the central nervous system, and the characteristic affections of the hearing and sight have not been observed under it. In man, very large quantities of benzoic acid and also of the ben- zoate of soda sometimes produce nausea and vomiting, the vomited matter rarely being tinged with blood. A certain sedative action on the central nervous system is also said to be observed, and an increased expectoration of mucus is produced in cases of bronchial irritation. The pulse is somewhat accelerated. In the dog, tremors and convulsions have been observed, but are generally less marked than under carbolic acid. Ataxia, paresis, and eventually complete paralysis of the fore limbs, and later of the hind limbs and trunk follow, the temperature falls, and death occurs from asphyxia. The heart and respiration are first accelerated and then slowed, from a direct action on the heart and on the respiratory centre. Vomiting occurs when the acid or the salts are given by the mouth. Post-mortem the gastric mucous membrane has been found to be eroded and ecchymosed, even when the salts or acid have been injected subcutaneously or intravenously, so that the benzoates and benzoic acid would seem to have a specific action on the gastric mucous mem- brane quite apart from their irritant effects when applied locally. In frogs, fibrillary contractions and convulsions are observed, followed by weakness and paralysis of the spinal cord. Hemorrhages have also been found in the stomach when the drug was injected into a lymph-sac. Benzoic acid (C 6 H 5 COOH) combines with glycocoll in the body to form hippuric acid (C 6 H 5 CO NHCH 2 COOH), which is excreted in the urine. Some of the benzoic acid escapes in the urine unchanged, however, the proportion of hippuric acid formed apparently varying with the general health and the condition of the kidneys, and also with the dose administered. After large doses a reducing body has been observed in the urine, presumably glycuronic acid. Traces of benzoic acid are found in the saliva of the dog after its administration, but it does not seem to be excreted here in man. In birds, benzoic acid is excreted by the kidneys as ornithuric acid (C 19 H 20 N 2 O 4 ), from which benzoic acid can be split off, leaving ornithin. Benzoic acid often in- creases the nitrogen eliminated in the urine, so that in these cases it ANTISEPTICS OF THE AROMATIC SERIES. 419 augments the decomposition of the proteids like salicylic acid ; in other investigations no material change has been observed, probably because the benzoic acid was changed too rapidly to hippuric acid to admit of its action on the metabolism being developed. It differs from salicylic acid in reducing the uric acid excretion. Some diuresis occurs after benzoic acid. Some diminution in the double sulphates and the indican of the urine have been observed after the administration of benzoic acid by the mouth, so that it apparently lessens the putrefaction in the in- testine. Cinnamic acid (C 6 H 5 -CH=CH-COOH) seems to resemble ben- zoic acid in its pharmacological characters, but has not been so care- fully examined. It increases the leucocytes of the blood and the uric acid of the urine to a marked degree. PREPARATIONS. ACTDUM BENZOICUM (U. S. P., B. P.) (C 6 H 5 COOH), benzoic acid or flowers of benzoin, is prepared from benzoin by sublimation, or from toluol, and consists of white, feathery crystals, almost odorless, with a warm acid taste, very insoluble in water, soluble in alcohol, ether, fixed and volatile oils and in alkaline solutions. 0.3-1 G. (5-15 grs.), in powder or pill. Trochiscus Acidi Benzolci (B. P.), each contains \ gr. Sodii Senzoas (U. S. P., B. P.), easily soluble in water. 0.3-2 G. (5-30 grs.), in solution. Lithii Benzoas (U. S. P.), 0.3-2 G. (5-30 grs.). Ammonii Benzoas (U. S. P., B. P.), 0.3-2 G. (5-30 grs.). Benzoic acid is also contained in paregoric. The Balsams are mixtures of resin, volatile oils, benzoic and cinnamic acids and their esters and small quantities of other aromatic bodies. Benzoinum (U. S. P., B. P.), benzoin, a balsam obtained from Styrax Ben- zoin and probably from other species, varies in its composition with its place of origin, but contains much less cinnamic acid than the other balsams. Styrax (U. S. P.), Styrax Pr¶tus (B. P.), or storax, a balsam prepared from the inner bark of Liquidambar orientalis, contains resins, cinnamic acid and its esters. Tinctura Benzoini (U. S. P.), 2-4 c.c. (30-60 mins.). TINCTURA BENZOINI COMPOSITA (U. S. P., B. P.) contains, in addition to benzoin, storax, aloes and balsam of Tolu, and was formerly known as Bal- samum Traumaticum. A number of old remedies resembled it in composi- tion, such as Friar's balsam, Turlington's balsam, Jesuits' drops, etc. 2-8 c.c. (30 mins. -2 fl. drs.). BALSAMUM PERUVIANUM (U. S. P., B. P.), Balsam of Peru, a balsam ob- tained from Toluifera Pereirse (U. S. P.), or Myroxylon Pereirse (B. P.), con- tains cinnamic and benzoic acids (traces) and their esters, and resins. Ap- plied externally, either alone or in alcoholic solution. 0.3-1 c.c. (515 mins.). Balsamum Tolutanum (U. S. P., B. P.), Balsam of Tolu, a balsam obtained from Toluifera Balsamum or Myroxylon Toluifera, resembles balsam of Peru in composition, but contains more benzoic acid. 0.3-1 G. (5-15 grs.). SYRTJPUS TOLUTANUS (U. S. P., B. P.), 2-4 c.c. ($-1 fl. dr.). Tinctura Tolutana (U. S. P., B. P.), 1-4 c.c. (15-60 mins.). Therapeutic Uses. Benzoic acid and its sodium salt have been sug- gested as antiseptics and seem to be quite as satisfactory as salicylic 420 ORGANIC DRUGS ACTING AFTER ABSORPTION. acid, but have never been widely employed. Benzoin and the balsam of Peru are used extensively in parasitic skin diseases, especially in scabies. Internally the benzoates have been employed as substitutes for salicylic acid in acute rheumatism, but have not proved so efficient in general. The lessened putrefaction in the bowel after benzoic acid suggests its use as an intestinal disinfectant, and it has been adminis- tered as an antiseptic and slight irritant in diseases of the genito-uri- nary tract, such as cystitis and gonorrhea. It was formerly supposed that benzoic acid lessened the uric acid excretion and dissolved the uric acid deposits in the bladder and tissues by forming hippuric acid, but this is now recognized to be erroneous, and the treatment of gout and other diseases based on this theory may be considered obsolete. The lithium benzoate of the U. S. P. is a survival of this treatment, lithium being credited with special solvent properties. Benzoic acid is still used as an ingredient in expectorant mixtures, in which however it is generally prescribed as the simple or com- pound tincture of benzoin, or as one of the Tolu preparations. It is said to be beneficial in cases in which the mucus is tenacious and is coughed up with difficulty. The syrup of Tolu may be regarded simply as a flavoring ingredient, for it contains too little of the balsam to have any other effect. Balsam of Peru and pure cinnamic acid have been administered by hypo- dermic and intravenous injection and by the mouth in pulmonary tubercu- losis, in the belief that they would induce irritation, inflammation and subsequent cicatrization of the tubercular nodules, but there is no reason to suppose that they have any such effect, and the treatment has never ad- vanced beyond the experimental stage. When the balsams are administered in large quantities, the addition of an acid to the urine is followed by the formation of an abundant precipitate in some cases, and this has given rise to the belief that they tend to irritate the kidneys. The precipitate appears to be not albumin but the resin in most cases, however, for it is dissolved by the addition of alcohol. BIBLIOGRAPHY. Robert u. Schulte. Schmidt's Jahrb., clxxxv., p. 12. Salkowski. Festschr. f. Leyden, ii., p. 25. C. Virchow. Ztschr. f. phys. Chem., vi., p. 78. Stockman. Brit. Med. Journ., 1890, i., p. 1365. Kumagawa. Virchow's Arch., cxiiL, p. 134. Brdutigam u. Nowack. Centralbl. f. klin. Med., 1889, p. 409. Richter u. Spiro. Arch. f. exp. Path. u. Pharm.,xxxiv., p. 289. Wiener. Ibid., xl., p. 313. Pribram. Ibid., 1L, p. 372. Lewandowsky. Ztschr. f. klin. Med., xl., p. 202. Ulrici. Arch. f. exp. Path. u. Pharm., xlvi., p. 321. Nitrobenzol Compounds. The nitrobenzol bodies are chiefly of interest because they have often given rise to poisoning of late years from their extensive use in chemical manufactures and to flavor alcoholic liquors. They are readily absorbed from the skin and seri- ous symptoms have followed the wearing of clothing dyed with them. In man nitrobenzol causes a grayish-blue, cyanotic color of the skin and visible mucous membranes, often with nausea, vomiting, great muscular weakness, marked ANTISEPTICS OF THE AROMATIC SERIES. 421 dyspnoea, delirium, and some convulsive movements of the face and jaws, less frequently of the whole body. Total unconsciousness and coma are followed by arrest of the respiration. These effects are due in part to changes in the blood, in part to central nervous action, in which stimulation and paralysis seem to follow one another. The blood is found of a chocolate-brown color, and some of the red cells are either deformed or entirely destroyed. Examined with the spectroscope, methaBmoglobin is very often found in it, while in other cases an absorption line is observed between the yellow and the red, which does not seem to corre- spond to that of any of the ordinary hemoglobin products, and has there- fore been called the nitrobenzol-ha3moglobin line. The blood contains a much smaller amount of oxygen than normally, in some cases only one per cent, instead of seventeen, and artificial respiration or even shaking the blood in air fails to oxidize it further, as the combination of nitrobenzol and haemoglobin seems to be incapable of absorbing oxygen. Similar changes may be produced in venous blood outside the body by shaking it with nitro- benzol. These changes in the blood are the cause of the cyanosis, and the imperfect oxidation of the tissues leads to the appearance of a number of abnormal products in the urine, such as haematoporphyrin. In animals a gastro- intestinal catarrh is almost constantly produced unless the intoxication is very acute, and this occurs even when the poison is inhaled or injected subcutaneously. Metadinitrobenzol (C 6 H 4 (NO 2 ) 2 ) has repeatedly given rise to poisoning in the manufacture of the modern explosives, such as roburite and securite. In action it resembles nitrobenzol, but is more poisonous, and the gastric symp- toms are more marked. Amblyopia and a jaundice like coloration of the skin often occur from prolonged exposure to this poison. Picric Acid (C 6 H 2 OH(NO 2 ) 3 ) is an irritant to the skin and mucous mem- branes, and in large doses causes vomiting and often anuria and strangury. A characteristic symptom is the yellow, icteric color of the skin and mucous membranes, which is due not to true jaundice, but to the staining of the epithelium by the acid. It produces this coloration when taken internally, and itching is often complained of, and some eczema or erythema has been observed. Violent convulsions occur sometimes, in other cases collapse. The urine is yellow or red, and contains some casts but little or no albumin, and no bile, the absence of the last serving to diagnose the intoxication from jaundice. Picric acid tends to destroy the red cells of the blood in animals, but no marked diminution of these has been observed in man. It is excreted as picric and picramic acid (C 6 H 2 OH.NH 2 (NO 2 ) 2 ) in the urine. Picric acid has been used as a substitute for quinine in malaria, and as an antipyretic. An ointment containing it has been applied in some forms of eczema, but it gave rise to poisoning in one of the few cases in which it was thus employed. BIBLIOGRAPHY OF THE AROMATIC NITRO-BODIES. Starkow. Virchow's Arch., lii., p. 464. Hay. Practitioner, xxx., p. 326. Filehne. Arch. f. exp. Path. u. Pharm., ix., p. 329. Lewin. Virchow's Arch., Ixxvi. , p. 443. Stone. Jour. Amer. Med. Ass., Oct. 1, 1904. Schroederu. Strassman. Viertlj. f. ger. Med., 1891, i., Suppl., p. 138. Seek. Charite Annalen, xvii., p. 867. Munzeru. Palma. Zts. f. Heilk., xv., p. 185. Huber. Virchow's Arch., cxxvi., p. 240. Naphthylamine. Stern has observed a curious and almost unique series of symptoms after fae administration of several hydrated derivatives of /3-naphthylamine to mammals. The most interesting of these were dilation of the pupil and 422 ORGANIC DRUGS ACTING AFTER ABSORPTION. protrusion of the eyeball, and a very marked rise in the temperature, amounting in some cases to 4 C. The dilation of the pupil, which was not observed in the later experiments of Fawcett and White, is ascribed by Stern partly to local action on the dilator fibres or the terminations of the sympathetic nerves in the iris, but mainly to some central stimulation. The rise of temperature is produced in part by the output of heat being lessened through contraction of the cutaneous vessels, in part by increased oxidation in the tissues and augmented heat production. The contraction of the vessels is to be attributed chiefly to stimulation of the vaso-motor centres, although the drug seems to have some direct effect on the muscular walls of the vessels also. Cocaine has a somewhat similar but weaker action, but the naphthyl- amine compounds do not produce local anesthesia. BIBLIOGRAPHY. Stern. Virchow's Arch., cxv., p. 34, and cxxi., p. 376. Fawcett and White. Journ. of Physiol., xxi., p. 435. Toluylendiamine. Toluylendiamine (C 6 H 3 CH 3 (NH 2 ) 2 ) has never been used in therapeutics, but it is of importance from the light which it has thrown on some forms of jaundice. Stadelmann found that its administration in dogs produced the typical symptoms of icterus, while in cats the icterus was less marked, but very large quantities of haemoglobin were excreted in the urine. The expla- nation of this action is the destruction of the red cells in the blood, which leads in the dog to the formation of large amounts of bile pigments in the liver. Some of this pigment is reabsorbed from the bile vessels and leads to typical jaundice. The absorption is promoted by a curious increase in the mucus secretion of the bile ducts, which renders the bile more viscous, and by thus delaying its evacuation into the intestine favors its absorption into the blood. This increased mucus formation is believed to be due to the action of the poison on the secretory cells of the larger bile ducts. The formation of bile pigment from haemoglobin liberates large quantities of iron, which seems to be stored in the liver, spleen and bone marrow. In the cat the haemoglobin is not so largely formed into bile pigment, but escapes in the urine. In both animals some methaemoglobin is probably formed. 1 BIBLIOGRAPHY. Stadelmann. Arch. f. exp. Path. u. Pharm., xiv., pp. 231 and 422; xxiii., p. 427. Engel u. Kiener. Comptes rend, de 1'Acad., cv., p. 465. Mohrberg. Arb. a. d. pharm. Inst. zu Dorpat, viii., p. 20. Benzol. Benzol, or benzene, is much less poisonous than its hydroxyl com- pounds, but may give rise to symptoms resembling those of phenol when it is inhaled in large quantities. It was at one time suggested as a general an- aesthetic, but the preliminary excitement is very much greater than that seen in the use of chloroform or ether, and partakes much more of a convulsive character. Even after unconsciousness and anaesthesia is attained, the char- acteristic muscular tremor of the aromatic compounds continues. In some animals it produces violent and prolonged convulsions, with only partial loss of sensation, and even large quantities do not cause the complete relaxation of the muscles requisite for surgical operation. It seems to have little or no irritant action on the alimentary canal or kidneys in animals, and is excreted 1 A somewhat similar action follows the administration of Cephalanthin, the active principle of Cephalanthus occidentalis, Button-bush or Swamp dogwood (Mohrberg). FORMALDEHYDE. 423 in part by the kidneys as phenol double sulphate, in part unchanged by the lungs. Santesson states that haemorrhages occur very frequently in fatal poison- ing in man, and found the same result in experiments on rabbits ; he ascribes it to fatty degeneration of the arterial walls, which was well-marked in most of his experiments. A number of cases of fatal intoxication are on record, some of them arising from the drug being swallowed by suicides, but most of them from the accidental inhalatipn of large quantities in india-rubber fac- tories. Animals exposed to benzol vapor do not seem to absorb enough to be seriously poisoned, but when it is injected subcutaneously or applied over a large skin area, it proves fatal to them. The benzol of the B. P. contains toluene and is used only for pharmaceutical purposes. BIBLIOGRAPHY. Santesson. Arch. f. Hygiene, xxxi., p. 336. Skand. Arch. f. Physiol., x., p. 1. Chassevant. Arch, de Pharmacody nam. , ii., p. 235. Pyoctanine. Several of the dyes derived from aniline are used to stain pathogenic germs and to differentiate them from each other. This suggested to Penzoldt the idea that these bodies, having a distinctly greater affinity for the microorgan- isms than for the tissues surrounding them, might be used as antiseptics or disinfectants, and Stilling introduced several of them into therapeutic use under the name of pyoctanines. Some of these dyes have been found to have a certain antiseptic action , but the hopes that were formerly entertained as to their specific action have proved delusive, and their use in medicine (chromotherapeutics) is now very limited, and promises to fall into oblivion. MethylthionincB Hydrochloridum (U. S. P.), methylene blue, a dark green pow- der, readily soluble in water and alcohol, forming a deep blue solution. Dose, 0.25G. (4grs.). XXV. FORMALDEHYDE. It has recently been shown by numerous investigators that formal- dehyde (HCOH), the aldehyde derived from the oxidation of methyl alcohol, is a very powerful germicide, while it is only slightly poison- ous to the higher animals. The aldehyde is a colorless gas and has been used either in solution in water (formaline) or as a vapor. As a germicide it is estimated to be equally efficient with corrosive subli- mate, and its volatility enables it to penetrate much more rapidly, so that it may be used for purposes for which the latter is unsuitable. On the other hand, its volatility and irritant action preclude its use as an antiseptic to prevent the growth of microbes in wounds. Action. The vapor is very irritant when inhaled, causing stinging and prickling in the nose and throat, salivation and tears, and bronchial irritation and catarrh. In the few cases of poisoning in man recorded, the symptoms were those of gastric irritation and consequent collapse. When swallowed by animals the watery solution produces nausea and vomiting, which are followed by narcosis, coma, and in the rabbit by convulsions and opisthotonos. The respiration in the dog is very greatly accelerated some time before death, while in the rabbit this is not so marked or is entirely absent. The blood-pressure is increased at first and the heart is slow, presumably from direct or indirect stimu- lation of the medullary centres. Part of the formaldehyde absorbed 424 ORGANIC DRUGS ACTING AFTER ABSORPTION. has been shown to pass through the tissues unchanged and to be excreted in the urine, and it is possible that the whole of it escapes in this way. The symptoms induced in animals by formaldehyde are for the most part due to the intense local irritation and inflammation, but in addition a specific destructive effect has been observed in the liver and kidney (Fischer). The powerful action of formaldehyde on microbes and on mucous membranes is believed by Loew to be due to its combining with some amide group in the proteids, and as a matter of fact, a number of changes have been described in the reaction of proteids exposed to formaline. For example, egg albumin and serum to which formal- dehyde solution has been added are not precipitated by heat and are less easily digested by ferments, while casein is not coagulated by the rennet ferment. Some of the ferments (pepsin and diastase) are not affected by the presence of formaldehyde, while trypsin and papain lose their activity wholly or in part. Benedicenti states that formaldehyde is a blood poison, causing alter- ation in the form of the cells and leading to the formation of haematin. He is disposed to look upon this effect as the chief factor in the in- toxication. PKEPARATIONS. Formalin, LIQUOR FORMALDEHYDI (U. S. P.), a solution of formaldehyde in water containing not less than 37 per cent, of the gas, which may be obtained from it by distillation. Paraform, a solid polymer of formaldehyde, which is decomposed by heat and liberates the formaldehyde in gaseous form. Some formaldehyde may be formed by the incomplete combustion of methyl alcohol, and several lamps have been devised with this object in view, but have not proved entirely satisfactory. Uses. Formaldehyde is too irritant to admit of its use as an anti- septic in medicine and surgery, but it has been largely employed to disinfect instruments, furniture, clothes and rooms, which cannot be sterilized by heat. Diluted formaline (4 per cent.) may be used for some of these purposes, or the vapor may be disengaged by distillation from formaline, by heating paraform, or less efficiently by the partial combustion of methyl alcohol. Large rooms filled with formaline vapor and left for some hours are found to be almost completely steril- ized, so that cultures of the pathogenic microbes exposed in them cease to grow even when removed from the atmosphere. The higher animals are much less affected. Novy recommends that the room to be disin- fected be made as nearly air-tight as possible, and the formaldehyde be distilled into it through the key-hole of the door. He states that the gas disengaged from 150 c.c. (5 oz.) of 40 per cent, formaline is suffi- cient for each 1000 cubic feet of space, if the room be closed for 10 hours. The odor of formaline may then be removed by sprinkling ammonia solution with which it forms a solid combination. Formaldehyde has frequently been added to food, especially to milk, as a preservative. Tunnicliffe and Rosenheim found that added to milk in the proportion of one to five thousand, formaldehyde did not seem FORMALDEHYDE. 425 to be deleterious to healthy children, but in the case of a weakly child the proteid waste was increased, and it is certainly not to be regarded as a harmless method of preserving food. Formaldehyde is not alone in its germicidal action, although it is much more powerful than the other less volatile and less active aldehydes, such as acetaldehyde. Urotropine. Urotropine, or hexamethylenamine ((CH 2 ) 6 N 4 ), has no important action itself, but is of interest from its liberating formaldehyde in the course of its excretion by the kidney. The formaldehyde escapes in the urine along with some unaltered urotropine, and acts as a disin- fectant or antiseptic in the urinary passages ; it seems superior to any other urinary antiseptic, microbes in the urine decreasing in number or sometimes disappearing altogether within a few hours of its adminis- tration. No symptoms arise from ordinary doses of urotropine, but large quantities have occasionally given rise to pain and discomfort in the bladder, and more rarely to haematuria. Formaldehyde forms some sol- uble combinations with uric acid, and this suggested the use of urotro- pine in gravel, calculus, gout, and similar conditions, but the results have been disappointing. HEXAMETHYLENAMINA (U. S. P.), UROTROPINE ((CH 2 ) 6 N 4 ), is a white crystalline powder, very soluble in water. Dose, 0.20.6 G. (3-10 grs), to be taken in a glass of water. Urotropine is used in cystitis and urethritis and to destroy typhoid bacilli in cases in which they are eliminated by the kidney. It may also be given as a prophylactic before a catheter is passed. Numerous compounds of urotropine have been introduced of late years by rival manufacturers, but none of these has proved equal to the original drug. BIBLIOGRAPHY. Loew. Ein natiirliches System der Giftwirkungen, Miinchen, 1893, p. 58. Koch. Amer. Journ. of Phystol., vi., p. 327. Fischer. Journ. of Exp. Med., vi., p. 487. Dieudonne. Arbeit, a. d. Gesundlieitsamt., xi., p. 534. Mosso et Paoletti. Arch. Ital. de Biol., xxiv., p. 321. Tollens. Bericht. der Deuts. Chem. Gesellsch., 1895, p. 261. Pohl. Arch. f. exp. Path. u. Pharm., xxxi., p. 295. Ermengem et Sugg. Arch, de Pharmacodynam., i., p. 141. Armison. Zts. f. Hygiene, xxv., p. 168, 1897. Strilver. Ibid., p. 357. Benedicenti. Arch. f. [Anat. u.] Phys., 1897, pp. 210 and 219. Novy and Waite. Medical News, Ixxii., p. 641 (1898). .Bliss and Novy. Journ. of Exp. Med., iv., p. 47. Tunnicli/e and Rosenheim. Journ. of Hygiene, i., p. 321. Urotropine. Nicolaier. Zts. f. klin. Med., xxxviii., p. 350 ; Deutsch. Arch. f. klin. Med., Ixxxi., p. 181. Stern. Leyden's Festschrift, 1902, i., p. 583. Richardson. Journ. of Exp. Med., iv., p. 19. Sachs. Wien. klin. Woch., 1902, p. 442. Fuchs. Ibid., 1903, p. 170. 426 ORGANIC DRUGS ACTING AFTER ABSORPTION. XXVI. CAMPHOR. Some of the volatile oils deposit crystalline substances or stearop- tenes after standing for some time, especially when they are exposed to cold. As a general rule these bodies are present in only small amount, and have not been investigated apart from the volatile oils, of which they form constituents ; but a few of them have attracted at- tention in therapeutics, not only on account of their local effects, which have been described under the volatile oil group (see page 61), but also because of their action in the tissues after absorption. The chief of these is Camphor, which has been used in Chinese medicine for many centuries, and which has also played a considerable role in Western therapeutics. It is derived from the Cinnamomum camphora of China and Japan, and possesses the formula C 10 H 1G O ; it is a benzol derivative containing methyl and propyl, in so far resembling the terpenes, from which, however, it differs in the presence of a ketone (= CO) link. Another body closely resembling ordinary camphor is Borneol or Borneo- camphor (C 10 H 1K O), which is derived from the Dryobalanops aromatica, and which apparently differs from ordinary camphor in containing the group (= CHOH) instead of (= CO). Ngai- camphor, which is obtained from Blumea balsamifera, is very closely related to borneol. Another stearoptene which has been used in medicine apart from the volatile oils, is Menthol (C 10 H 20 O), which is obtained from the oil of peppermint, and apparently contains a CHOH group like borneol, but is more completely hydrated. Borneol has been prepared synthetically from camphor, and menthol from menthane, which occurs in oil of peppermint. Thujon, an isomer of camphor, occurring in the oil of wormwood or absinth and in many other plants, has not been used in medicine, but is of great importance as the cause of epilepsy in chronic absinth drinkers. Several derivatives of camphor which have been examined, resemble it closely in pharmacological action. Monobromated Camphor (C 10 H 15 BrO) has been used in therapeutics, while Camphorol (C 10 H 16 O 2 ), Camphoric Acid (C S H U (COOH) 2 ), Amidocamphor (C 10 H 15 NH 2 O), Sorm/lamine (C 8 H U (CH 2 )- (CHNH 2 )) and some other derivatives have been the subjects of experi- mental investigation. All of these resemble each other very closely in the effects which they produce in the organism, although they vary in toxicity to some extent. Many of the volatile oils induce the same symptoms, but as these are used almost exclusively for their local action, it has been found advisable to treat them separately. The camphor group pre- sents analogies to the simpler bodies of the aromatic series, to which it is so nearly related chemically, and also to picro toxin. Symptoms. Camphor acts as an irritant to the skin and mucous membranes like the volatile oils, and has a hot, bitter taste, and induces in small quantities a feeling of warmth and comfort in the stomach, while after large doses nausea and vomiting may be caused by gastric irritation. It is rapidly absorbed and in large doses induces headache, a feeling of warmth, confusion, and excitement in man, with slowing of the pulse and flushing of the skin. This excitement may be shown in CAMPHOR. 427 hilarity and delirium with hallucinations, in restlessness, or in sudden violent movements, which pass into epileptiform convulsions. These alternate with pauses of quiet and^mconsciousness, which become longer until the patient sinks into complete stupor. In some cases of poisoning no excitement is observed, the patient falling into a condi- tion of drowsiness, unconsciousness and stupor immediately. In the lower mammals, camphor induces very similar symptoms, wild excite- ment and epileptiform convulsions, followed by depression, stupor, collapse, and death from failure of the respiration. Not infrequently however, the respiration ceases during a convulsion and fails to return when it passes off. In the frog no excitement is observed except from the local irri- tation ; the animal falls into a condition of depression, in which no spontaneous movements are made, although the reflexes seem to be little affected at first. Later, the reflexes disappear and the animal lies completely paralyzed. Action : Central Nervous System. Camphor first depresses the brain in the frog, later the spinal cord, and last of all the terminations of the motor nerves, and the spontaneous movements cease first, therefore, then the reflexes disappear, and finally the muscles fail to contract when the peripheral nerves are stimulated. The cord is capable of conduct- ing impulses from the brain after the reflexes are paralyzed, so that camphor would seem to interrupt the connection between the sensory and the motor cells earlier than that between the motor columns and the cells of the anterior horn (contrast strychnine). Although camphor fails to elicit convulsions in the frog, thujon often induces violent spasms, which appear to arise from stimulation of the spinal cord and medulla oblongata. The exact action of camphor on the spinal cord in mammals is not finally determined, for Stockman found that the reflexes were not increased in mammals by camphor, and he holds that the spinal cord is not primarily stimulated by ordinary camphor, and is in fact depressed by borneol. On the other hand, Gottlieb and Lapin assert that the reflexes are increased by camphor in mammals in which the medulla oblongata has been divided, and that in the bird this increased irritability may even give rise to con- vulsions. According to them, the spinal cord is finally depressed in mammals by very large doses of camphor, but only after stupor and coma indicate commencing paralysis of the cerebrum. The convulsions in mammals are certainly not due to any action on the spinal cord, but to stimulation of the higher areas of the nervous axis. The cerebral cortex is involved in the action, for the convulsions are less marked on its removal ; but in the lower mammals the chief action seems to be exerted on the nervous centres situated between the cerebral peduncles and the medulla oblongata. It is not improbable that in man the cerebral action may be more marked than that on the lower areas, for on descending lower in the scale it is found that the cere- bral action becomes less evident ; thus in birds the removal of the cere- brum seems to have no effect on the convulsions. The loss of con- 428 ORGANIC DRUGS ACTING AFTER ABSORPTION. sciousness and the stupor observed in man and the higher animals point to a final paralysis of the cerebral cortex. The Terminations of the Motor Nerves are paralyzed in the frog by large doses of camphor, but not in mammals. The Muscles them- selves are weakened and paralyzed when they are directly exposed to its solutions or vapor. The Heart is sometimes slowed by camphor and its allies in man and animals, but is generally little affected in either strength or rate. The frog's heart also beats more slowly, but the contractions are stronger and fuller according to most observers, although Lewin found both its absolute force and pulse volume lessened ; these changes arise from action on the muscle fibres, which are rendered more irritable, so that muscarine fails to arrest the frog's heart after camphor (compare physostigmine, pp. 320, 324). In some mammals the Blood-pressure is slightly increased by cam- phor, in others great variations occur, a very marked rise being observed during the convulsive attacks, while in the interval it falls to below the normal height ; these variations indicate that the vaso-motor centre is involved in the action of the drug, for they persist when the muscular contractions are eliminated by the injection of curara. The peripheral vessels have been found to be dilated by camphor solutions perfused through them, and this action may explain the slight fall in pressure often seen after absorption of the drug. This slight dilatation of the vessels is the only change in the circu- lation observed after camphor, unless when quantities sufficient to cause convulsions are injected. The Respiration is somewhat slower and deeper than normal, but this alteration is generally insignificant. During the convulsions it is ar- rested, and in the intervals may be accelerated from the muscular ex- ertion during the spasms. The normal Temperature is not affected by camphor, but in fever it acts as an antipyretic, like many other aromatic bodies. Camphor is partially oxidized in the tissues, forming camphorol (C 10 H 16 O 2 ), this change perhaps being analogous to that observed in the aromatic hydrocarbons and phenols. It is Excreted in the urine 1 in combination with glycuronic acid, as a- and /9-camphoglycuronic acid, and also in part in combination with a nitrogenous body, which is prob- ably uramidoglycuronic acid. Camphorol acts like camphor, but its glycuronic acid combinations are inactive, so that the effects of cam- phor pass off quickly in such animals as the dog, in which these com- binations are rapidly formed. Camphor is possessed of some antiseptic action, although it is much weaker than some of the bodies of the carbolic acid group, and also than many of the volatile oils. Leucocytes cease their movements at once when exposed to camphor solutions or vapor, and Darwin found that it acts as a stimulus to the tentacles of Drosera, an insectivorous 1 Menthol is said to be excreted in small quantities in the bile. CAMPHOR. 429 plant, and apparently renders them more sensitive to mechanical irri- tation. Camphor produces redness and a feeling of warmth when rubbed into the Skin. Sometimes, however, a distinct sensation of cold may be experienced, provided the rubbing is not too energetic. Menthol generally induces this feeling of cold, accompanied by more or less prickling, and afterwards by heat and burning. The cold is not due to cooling of the skin, for the vessels of the part are dilated, and the thermometer indicates a higher skin temperature there than in other parts of the body. It has been ascribed to menthol being more irritant to the terminations of certain nerves which convey the sensation of cold than to those of the heat nerves and pain nerves, but this is denied by Rollett who states that menthol acts only on the terminations of the nerves of common sensation or pain. A feeling of numbness and par- tial anesthesia follows its application after some time, and a ten per cent, solution has been found to produce anaesthesia of the cornea, which, however, is preceded by pain and smarting. The action of borneol, menthol, bromated camphor, camphorol and cam- phoric acid is almost identical with that of camphor itself. Borneol is less irritant locally, and the convulsions are less severe than after camphor, so that animals seldom die during the convulsive stage, and may remain in a state of stupor and collapse for one or two days before the respiration finally ceases. After menthol, the convulsions are even less developed than after borneol. Both of these are excreted in combination with glycuronic acid. Bromated camphor seems to resemble borneol more closely than camphor or menthol, while camphoric acid and amido-camphor produce symptoms sim- ilar to those of camphor, but are much less powerful. Camphoric acid lessens the secretion of perspiration by paralyzing the terminations of the secretory nerves in the same way as atropine and agaricin. PREPARATIONS. Camphora (U. S. P., B. P.) (C 10 H 16 0), Laurel camphor, a stearoptene ob- tained from Cinnamomum Camphora, forms white translucent, crystalline masses, which are almost insoluble in water but dissolve readily in alcohol, ether, chloroform, fixed and volatile oils. 0.1-0.6 G. (2-10 grs.), in emulsion or pill. Aqua Camphors (U. S. P., B. P.). SPIRITUS CAMPHORS (U. S. P., B. P.), 0.3-2 c.c. (5-30 mins.). LINIMENTUM CAMPHORS, camphorated oil (U. S. P., B. P.). TINCTURA CAMPHORS COMPOSITA (B. P.), paregoric, contains 1 part of morphine in 2000, i. e., each fluid drachm is equivalent to J- grain of opium. i-1 fl. dr. lAnimentum Camphor se Ammoniatum (B. P.), compound camphor liniment. Camphor is also an ingredient in the camphorated tincture of opium, or paregoric (U. S. P.) and in soap liniment and chloroform liniment. Camphora Monobromata (U. S. P.), monobromated camphor (C 10 H 15 BrO), consists of colorless crystals which are insoluble in water, soluble in alcohol and ether. 0.3-1 G. (5-15 grs.), in emulsion or pills. Menthol (U. S. P., B. P.) (C 10 H 20 O), a stearoptene obtained from the official oil of peppermint or from Japanese or Chinese oil of peppermint, con- sists of colorless crystals slightly soluble in water, freely soluble in alcohol or ether. It is used externally in alcoholic solution or moulded into sticks and pencils, which are rubbed on the affected part. 430 OROANTC DRUGS ACTING AFTER ABSORPTION. Emplastrum Menthol (B. P.). ACIDUM CAMPHORICTJM (U. S. P.) (H 2 C 10 H 14 O 4 ), an acid obtained by the oxidation of camphor ; forms colorless crystals slightly soluble in water. Dose, 1-2 G. ( 15-30 grs.). Borneol or Borneo camphor (C 10 H 18 O), a stearoptene obtained from Dryo- balanops Camphora, resembles camphor in appearance and solubility, but has not been used in therapeutics and is not official. Therapeutic Uses. Camphor is used externally in the form of the liniment or spirit as a mild rubefacient in bruises and sprains, and also to destroy parasites. Internally the spirit is prescribed as a carminative and as an intestinal disinfectant. Its administration for the latter purpose has been shown to be followed by a diminution of the double sulphates of the urine, so that it seems to retard the putre- faction in the bowel to some extent. The spirit is frequently given to prevent " chill," and may relieve the congestion of internal organs through dilating the skin vessels. It was formerly administered in cases of abnormal irritability of the central nervous system, such as epilepsy and various other forms of convulsions, including those produced by strychnine, but its action would seem to contraindicate its use here and camphor is scarcely prescribed in these cases now. It has been used, apparently with success, as a stimulant to the cen- tral nervous system in unconsciousness and collapse arising from dif- ferent causes, and in the depression and weakness of acute fevers. In many of these cases, a marked improvement in the pulse has been ob- served after camphor ; this, like the similar improvement seen after alcohol, may perhaps be explained by its action as a local stomachic irritant producing changes in the circulation reflexly. Solutions of camphor have been injected subcutaneously in these cases, but they cause pain and swelling at the point of injection. Camphor is almost entirely insoluble in watery fluids and is apparently absorbed slowly and with difficulty in some conditions, and this may explain the absence of effect in many cases of collapse treated with it. Camphor is often prescribed in expectorant mixtures, especially in combination with opium, as in paregoric. It has been advised in hysteria, and both as an aphrodisiac and as an anaphrodisiac. Any effect in these conditions must probably be ascribed rather to hypnotic suggestion than to the real action of the drug. Menthol is used almost exclusively for its effects on the sensory nerve terminations, and is applied by rubbing the crystals or sticks on the skin in cases of headache and neuralgia. Camphoric acid has been found to lessen the night sweats of phthisis and is given for this purpose in powder in doses of 1-2 G. It pos- sesses the advantage over atropine of acting only on the sweat glands in the dose given, and on the other hand has no such action on the digestion as is sometimes complained of when agaricin has been pre- scribed. Camphoric acid is slowly absorbed and ought to be given an PICROTOXIN. 431 hour or more before retiring. It has also been used as an antiseptic, but is very much less efficient than salicylic or carbolic acid. Borneol and monobromated camphor are entirely superfluous. The latter was at one time used as a sedative in nervous excitement, but does not seem to have been at all beneficial and has fallen into disuse. BIBLIOGRAPHY. Hoffmann. Inaug. Diss., Dorpat, 1866. Rovighi. Zts. f. phys. Chem , xvL, p. 20. Schmiedeberg u. Meyer. Ibid., iii., p. 422. Stockman. Journ. of Physiol., ix., p. 65. Edinburgh Med. Journ., 1897, i., p. 45. Lewin. Arch. f. exp. Path. u. Pharra., xxvii., p. 226. Gottlieb. Ibid., xxx., p. 31. Meyer. Ibid., xxix., p. 438. Wiedemann. Ibid., vi., p. 216. Goldscheider. Arch. f. Anat, u. Phys., 1886, p. 555. Rollett. Pfliiger's Arch., Ixxiv., p. 418. JBourneville. Practitioner, xiii., p. 112. Lawson. Ibid., xiii., p. 324 ; xiv., p. 262. Lapin. Inaug. Diss., Dorpat, 1893. Winterberg. Pfliiger's Arch., xciv.. p. 455. Boehrn. Inaug. Diss., Halle, 1879. (Absinth.) Magnan. Compt. rend, de 1'Acad., Ixviii., p. 825. (Absinth.) Hildebrandt. Arch. f. exp. Path. u. Pharm., xlviii., p. 451. (Thujon.) Musk, or moschus, is the dried secretion of the preputial follicles of Moschus moschiferus, the musk deer of Thibet. It forms a dark, reddish-brown, crum- bling mass, with a very strong characteristic odor. About 10 per cent, is sol- uble in alcohol, about 50 per cent, in water. Musk has long been reputed to have a very powerful action in collapse, but is so rarely procurable at the present day, except in a very much adul- terated form, that it is comparatively seldom used. Very little is known with certainty as to its composition, and the odoriferous matter, which is believed to be the active principle, has scarcely been examined. In some early investigations, musk was found to cause headache, giddiness and confusion, with a feeling of weight and uneasiness in the stomach ; later, depression and drowsiness, and eventually sleep. Tremors and even con- vulsive movements have also been observed, and the pulse is said to be ac- celerated and strengthened. Filehne found tremors and contractions of isolated muscle bundles pro- duced in the frog from the action of an extract, and concluded that the motor terminations were stimulated by it. On the other hand, Hermans, 1 who studied the subject more recently, could find no effects from the admin- istration of musk to men or animals. Moschus (U. S. P., B. P.) has been recommended in hysteria and in col- lapse, and is prescribed either as a powder, in doses of 0.5-1 G. , which may be given per rectum when swallowing is impossible, or in the form of the tincture of the U. S. P., in doses of 5 c.c. It is rarely used at the present time, and may be considered entirely superfluous. XXVII. PICROTOXIN. Picrotoxin is the best known member of a group of convulsive poi- sons, which resemble each other very closely in action, but of whose chemistry little is known beyond the fact that they are devoid of nitrogen. It is obtained from the Anamirta paniculata (Anamirta cocculus, Menispermum cocculus), and is a neutral indifferent body. Picrotoxin (C 30 H. M O 13 ) may be broken up into picrotoxinin (C 15 H 16 O 6 ), Inaugural Dissertation, Bonn, 1888. i 432 ORGANIC DRUGS ACTING AFTER ABSORPTION. which resembles it in its effects on animals, and picrotin (C 15 H 18 O 7 ), which is inactive. Other poisons resembling picrotoxin are Cicutoxln, derived from the Cicuta virosa, or water hemlock, and probably from other species of Cicuta, (Enanthotoxin, the active principle of (Enanthe crocata, water dropwort, or dead tongue, and Coriamyrtin, which occurs in several species of Coriaria, of which the best known is the Coriaria myrtifolia or currier's sumach. Another species of Coriaria affords the toot poison of New Zealand. Phyto- laccotoxin, which has been prepared irom a Japanese species of Phytolacca, resembles picrotoxin in its action and may probably be contained in the official (U. S. P.) Phytolacca decandra, or pokeberry. Lastly, a number of the members of the digitalis series may be decomposed into bodies which, devoid of the characteristic cardiac action of digitalis, produce the same symptoms as picrotoxin. Among these may be mentioned Toxiresin, ob- tained from digitoxin, Digitaliresin from digitalin, and Oleandresin from oleandrin. These bodies all produce powerful stimulation of the central nervous system, more especially of the areas around the medulla oblongata. The chemical connection between them and the members of the digitalis series has been mentioned already. It may be added that the two groups are similar in action in some respects, for although picrotoxin does not affect the heart and vessels in the same way as digitalis, the latter possesses the characteristic action of picrotoxin on the medulla oblongata, although in a weaker degree ; in fact, some of the remedies described under the digitalis series act as strongly on the central nervous system as on the heart. Picro- toxin resembles camphor also in its effects. Two alkaloids, Samandarine and Samandaridine, recently isolated by Faust from the skin of the newt ap- pear to resemble picrotoxin in their effects on animals. Symptoms. The symptoms, which are often somewhat late in ap- pearing, are very similar in all classes of vertebrates. In man vom- iting is not infrequently observed after members of this series, or the first symptoms may be salivation, acceleration of the respiration, and some slowness of the pulse and palpitation of the heart. A condition of stupor and unconsciousness follows and then a series of powerful convulsions, which, commencing in tonic spasms, soon change to clonic movements of the limbs and jaws. The respiration is inter- rupted during these spasms, but is reinstated during the intervals of quiet and collapse which follow them. The convulsions return after a short pause, and this alteration of spasm and quiet may continue for some time, although the respiration often fails to return after one of the spasms, and fatal asphyxia results. Similar effects are observed in the lower mammals. After a pre- liminary stage in which twitching of the muscles and vomiting often occur, and in which the respiration is accelerated, while the pulse is slow, a violent emprosthotonic convulsion sets in, but soon changes to clonic movements ; these may last for some time, but eventually become weaker and give place to a condition of quiet and depression. An increase in the reflex excitability is noticeable during this interval, the animal is easily startled and occasional twitching of the muscles may be observed. Very soon a second convulsion sets in, and this may be fatal from asphyxia, but the symptoms often continue for an hour or more, violent spasms alternating with periods of depression and collapse. In the frog clonic convulsions are also the chief feature PICROTOXIN. 433 of the intoxication. Very often the animal becomes distended with air during the convulsions, and gives a curious cry in releasing it. The heart is always slowed and may cease to beat altogether for a time. Action. The clonic convulsions of picrotoxin poisoning are al- together different from those of strychnine and other similar bodies, which induce prolonged tonic convulsions, and it was early surmised that the members of this series act on a different part of the Central Nervous System. The convulsions are found to persist in the frog after the cerebrum has been destroyed, and even when all of the brain above the medulla oblongata has been removed, although they are weakened by the destruction of the optic lobes. On the other hand, they disappear, or at any rate lose their typical character when the medulla oblongata is removed, so that it would seem that picrotoxin and its allies act chiefly on the medulla oblongata, while the spinal cord and the higher parts of the brain are comparatively little affected. Strych- nine, on the other hand, exercises its chief action on the spinal cord, while the other parts of the central nervous axis are less affected. It was formerly supposed that picrotoxin stimulated a " convulsion centre " in the medulla oblongata, but there is no reason to believe that any such definite area exists, and it would rather appear that intense stimulation of the medulla in general leads to clonic contractions of the muscles throughout the body. The effects of the stimulation of the individual centres in the medulla are seen in the acceleration of the respiration, in the slow pulse, which is due to inhibitory action, in a very marked rise of the blood-pressure, and in the vomiting and salivation. The medulla cblongata is not, however, the exclusive seat of action, for in many animals the reflexes are found to be increased when the medulla is severed from the cord, and this indicates that the spinal cord is also more excitable than normally. This action on the spinal cord is best seen in the fish and reptile, and is much less marked in the frog and mammals. In the former, picrotoxin causes convulsions even after the medulla oblongata is removed, but in the higher animals, in which the functions are more differentiated, it merely increases the reflexes or causes very slight convulsive movements ; and the higher the position in the scale of the organism, the more closely is the action of this series confined to the medulla oblongata. It may be questioned whether the higher divisions of the nervous axis are concerned in the picrotoxin intoxication, for though in some animals restlessness and increased spontaneous movements are seen, they may perhaps be the indirect results of the alterations in the respiration and circulation. The Heart is rendered slow by picrotoxin, and in the frog may come to a standstill during the convulsions. This is due principally to stimu- lation of the inhibitory centre in the medulla, since on division of the vagi the heart returns to almost its normal rate. Some direct depres- sion of the heart is observed after large doses, for the pulse remains slowed even after atropine or division of the vagi. This action on the 28 434 ORGANIC DRUGS ACTING AFTER ABSORPTION. heart is not similar to that characteristic of digitalis, as has been sup- posed, but is a paralysis such as is observed after many poisons (e. g.j chloral). In some cases acceleration of the heart is seen towards the end of the intoxication, and this has been supposed to be due to stimulation of the accelerating centre. Picrotoxin causes a very marked rise in the arterial tension from stimulation of the vaso-constrictor cen- tres in the medulla and upper part of the cord. The Respiration is accelerated before any convulsions set in, and in the intervals between the spasms is also very rapid, owing to the action on the centre. Late in the intoxication the breathing may become slow and labored, probably from approaching central paralysis. In the frog, spasm of the laryngeal muscles prevents the escape of air from the lungs, so that the animal becomes enormously inflated. The Vomiting often observed in man and the dog under picrotoxin is probably of central origin and not due to gastric irritation. The peripheral Nerves and Muscles do not seem to be affected by these poisons, with the exceptions of toxiresin and digitaliresin, which slightly lessen the irritability of the muscles. The fate of picrotoxin in the body and the way in which it is ex- creted are unknown. Like other convulsive poisons, it tends to lower the temperature when it is given in small quantities so that no con- vulsions follow. The convulsions of picrotoxin and its allies disappear when chloro- form or chloral is administered. On the other hand, the respiration, weakened by narcotic poisons such as chloral, is accelerated by picro- toxin, the blood-pressure rises, and the sleep is less prolonged. Ani- mals are not awakened at once from narcosis by picrotoxin, but coria- myrtin has this effect. Picrotoxin is not antidotal in morphine poisoning in animals, but may possibly be so in man (see page 213). PREPARATIONS. Picrotoxinum (B. P.), picrotoxin (C, H 84 O 18 ), a neutral principle obtained from Anamirta paniculata, slightly soluble in water, much more so in alcohol. 0.001-0. 003 G. ( which repre ~ therapeutic use of these drugs the slowing is not great enough to counterbalance the in creased output per beat, and a larger amount of blood is therefore driven into the aorta and pulmonary artery. The more complete contraction of the ventricle also causes a higher pressure in its interior than before, and the blood is therefore expelled into the vessels under greater pressure than normally. THE DIGITALIS SERIES. 443 The changes in the ventricle, then, are due to inhibitory activity and to direct cardiac action, the first tending to lessen the number of beats, to increase the relaxation of the fibres and to weaken the systole, and thus to diminish the output and efficiency of the heart ; the second tending to strengthen the systole and thus to augment the output, while also limiting the dilatation, which may increase or lessen the efficiency of the heart according to circumstances. In the auricles the same two agencies are found in opposition, the inhibitory stimulation and the muscular actions. Stimulation of the inhibitory nerves causes in the auricle more or less increase in the dila- tation, while it lessens the contraction considerably, and in fact may prevent it entirely. The muscular action of this series is the same here as in the ventricle, causing a tendency towards more complete systole and less complete relaxation. After small quantities, such as are used in medicine, the rhythm of the auricle is slow, like that of the ventricle, owing to the inhibition ; the relaxation is little changed, but, owing to the muscular action, the contraction is more complete. In but slightly larger quantities, however, the inhibitory action causes a less complete contraction, so that the work done by the auricle is actually less than before the injection. The rhythm of the different parts of the heart is exactly the same during this stage, and the changes seen in the right auricle and ventri- cle correspond to those in the left. Not infrequently a previously irregular heart becomes more regular under the influence of small doses of digitalis, and this has generally been regarded as the result of the inhibitory action, which lessens the irritability of the heart and thus reduces the tendency to premature contractions. But several investigators have recently shown that the same regularizing action is exercised by digitalis in the excised heart, when there could be no question of inhibition ; they therefore ascribe this result to some obscure changes induced by the muscular action of this series (Gottlieb and Magnus, Brandenburg). If larger quantities be injected, either the inhibitory or the muscular action may become markedly increased, and the appearance of the heart varies according to which of these predominates. It must be distinctly understood that the following symptoms betoken a grave condition of poisoning and are not met with in the therapeutic use of the series. In the second stage, the symptoms are due to excessive inhibitory activity, while the direct cardiac action is less developed. The rhythm of the ventricle, and consequently of the pulse, is very slow and irregular, as is always the case when the inhibitory apparatus is strongly stimulated (see Fig. 27, p. 289). During diastole the ven- tricle dilates more completely than usual, while its systole varies in strength. If the muscular action is well developed, it continues to empty itself more completely than usual, but very often the inhibition is so powerful that the muscular action is entirely concealed and the svstole is weaker and more blood remains at the end of the contrac- 444 ORGANIC DRUGS ACTING AFTER ABSORPTION. tion than before the drug was administered. As a general rule, how- ever, each beat expels more blood than normally, because the heart is engorged before the systole begins ; but the rhythm is so slow that the, output per minute and the efficiency of the heart as a pump is less than usual. This is the feature which differentiates the first from the second stage, in which the same factors are present ; in the first stage the efficiency of the heart, i. e., the amount of blood expelled per minute, is greater, in the second stage less than before the administra- tion of the drug. Not infrequently the auricle and ventricle beat in different rhythms, the ventricle developing a spontaneous rhythm which may be either faster or slower than that of the auricle. This is apparently due to the inhibitory action, which blocks the passage of impulses from the auricle to the ventricle, although the effect of the drug in increasing the irritability of the cardiac muscle may contribute to it by facilitat- ing the development of the spontaneous ventricular rhythm. The auricular contractions are much weaker than in the first stage, and even than in the normal heart, and may cease altogether for some time, while the chambers do not tend to dilate further as a general rule. Although the rhythms of the auricle and ventricle may differ at this stage, the two ventricles always beat in unison, and the changes in the strength of their contraction and in the extent of the relaxation are similar. This stage of excessive inhibition is not observed in every case of poisoning in animals, nor probably in man, although in the recorded instances of poisoning with the members of this series, it seems to have been present, as the pulse is said to have been very slow and irregular. FIG. 41. Tracing of the auricular (upper) and ventricular movements (lower) under digitalis, as the first stage passes into the second. During systole the levers move upwards, during diastole downwards. The rhythm of the two chambers is at first the same, but soon changes, the auricle maintaining its rapid beat while the ventricle becomes slow and irregular. At the end of the tracing the ventricle again becomes rapid, while the auricle becomes slow. The strength of the contractions and the extens of relaxation of the ventricle muscle remain little altered, while the auricle rapidly weakens in strength, but improves again at the end of the tracing. Therapeutic doses of these drugs never induce irregularity in them- selves, though the pulse is often irregular from disease in the cases in which they are prescribed. When in their therapeutic use irregular- THE DIGITALIS SERIES. 445 ity arises from their effects, the physician is inducing the second stage of poisoning, in which the efficiency of the heart is less than it would be without the drug, and the dose ought to be reduced at once. If the inhibitory mechanism is weak or is paralyzed by the preliminary injection of such drugs as atropine, the second stage is entirely absent. When very large quantities of any of this series are injected, the third stage sets in. It is preceded by the first for a short time, gener- ally by both first and second. In this stage the ventricular rhythm becomes very much accelerated, often beyond the normal, and even beyond that seen after paralysis of the inhibitory nerves. This ac- celeration has often been supposed to be produced by paralysis of the vagus, but this is not the correct explanation, for stimulation of this nerve sometimes still slows the heart and always causes dilatation The acceleration is really due to the drug increasing the irritability of the heart muscle to such an extent that the inhibitory apparatus is no longer able to hold it in check. The auricles also undergo the same changes. They begin to accel- erate their rhythm, and if the second stage has not developed, they continue in the same rhythm as the ventricle. If, however, the ven- tricular rhythm has been independent of the auricular in the second stage, the auricles are often later in being accelerated than the ven- tricles, because the inhibitory nerves act more strongly on them. The difference in rhythm of the two divisions leads to a very characteristic periodic variation in the strength of the contractions of both auricle and ventricle. This auriculo-ventricular arhythmia may continue for some time, but farther irregularities soon present themselves. At in- tervals, asystole of either ventricle or auricle ap- FIG. 42. pears, that -is, two con- * ' ' ' ' ' ' < > > > < i i . . . . . . . . tractions follow so rapid- ly on each other, that n the chamber has no time to dilate fully between 1 ft H them and no blood is ex- pelled by the second one. These asystolic contrac- tions become more nu- merous, and soon form groups of two or three, separated by other groups of ordinary contractions. ' ' ' j U ' ' " I The rhythm becomes Tracin g O f the ventricular movements in the last stage of more and more raDid di g italis poisoning. The lever moves upwards in systole. The 1.1 n n ' characteristic feature is the extreme irregularity, no two con- ana Other lOrniS Ol irreg- tractions resembling each other in form or streng'th. ularity appear, which it is impossible to describe here. Eventually the auricle generally passes into fibrillary contractions while the rhythm of the ventricle continues to increase, and the force of its contractions and the output of each 446 ORGANIC DRUGS ACTING AFTER ABSORPTION. beat decrease. The ventricle finally passes into fibrillary contractions also, and the circulation is arrested, after which the heart dilates to an extreme degree. All the features of the third stage are due to the poisons increasing the irritability of the heart muscle. This leads to acceleration of the beat, and, eventually, through the muscle of one pair of chambers being acted on more than that of the other, to arhythmia. The asys- tolic contractions are evidently of the same origin, and the final delir- ium is also to be ascribed to this action. Almost all the characteristic features of this stage may be imitated in the normal, unpoisoned heart by stimulating the different chambers by electric shocks ; the impulses which in the poisoned heart arise from its own excessive irritability are here given by the artificial stimuli, but the effect is the same. The output of the heart continues much augmented during the first part of the third stage, but, as the irregularity of the ventricles in- creases, and the asystolic contractions become more numerous, it be- comes less and eventually falls to zero when the heart passes into de- lirium. Throughout the whole course of the intoxication the ventricles beat in unison, no interventricular arhythmia, such as has been de- scribed by some authors, being noticeable at any stage.- The two auricles often differ somewhat in their rhythm in the third stage, and the rhythm of the ventricles may, as has been stated, be entirely dif- ferent from that of the auricles in either the second or third stage. The effects of digitalis on the mammalian heart therefore resemble in general those observed in the frog's. The contraction is not pro- longed, however, as it is in the latter, and the inhibitory mechanism plays a more important role. The irregular stage evidently corre- sponds in each, and the final delirium cord is in the mammal represents the continued contraction in the frog, the mammalian heart not being capable of a continued systole. The heart in mammals is generally found in a condition of diastole in cases of fatal digitalis poisoning, and this has been supposed to indicate a fundamental difference in the action of digitalis on the amphibian and mammalian heart. The dila- tation is not, however, a direct result of the digitalis but is probably induced by the poisons formed in the heart by its own activity. When the mammalian heart is excised and blood containing digitalis is per- fused through the coronary vessels, complete systolic standstill of the ventricle resembling that seen in the frog is often the final outcome. The Peripheral Vessels are affected in several ways by the members of this series. The increased output of the heart in the therapeutic stage augments the pressure in their interior, and it seems not unlikely that the vaso-motor centre is stimulated and that this causes a con- traction of the arterial walls. But in addition to these effects, the muscular ^wall of the arterioles is constricted by a direct action of the glucosides and the resistance to the flow of blood from the arteries to the veins is increased, which further raises the tension in the aorta and larger arteries. It seems likely that all the members of the group do not act equally at all three points, but very little is known defi- THE DIGITALIS SERIES. 447 nitely on the subject except that digitoxin acts more powerfully ou the vessels than some of the others, and that erythrophloeine acts more on the medulla and less on the heart than any other glucoside hitherto examined. All the digitalis bodies then increase the arterial blood-pressure partly through changes in the heart, and partly through contraction 01 the vascular walls. There is on the one side an unusually large amount of blood expelled by the heart, on the other, unusual resist- ance to its passage out of the arteries. And this appears to be the final result when digitoxin is injected. .But when strophanthin, digi- talin or convallamarin is used, a further complication arises, for these Tiave a somewhat less marked vascular action, and though the vessels of the !_ abdominal .organs are contracted in the~same way as by digi- FIG. 43. Leg iilMWiW^^ Tracings of the blood-pressure and the volume of the leg and of the spleen of the dog under stro- phanthus. The volume of the leg increases with the blood-pressure, i. e., the vessels of the leg are dilated ; that of the spleen diminishes, i. e., the vessels are contracted ; 10 mg. of strophanthus were injected intravenously at a, followed by 5 nig. at b. (GOTTLIEB and MAGNUS.) toxin^ those of the extremities dilate. This dilatation is partly owing to the increased pressure in the interior overcoming the contraction of the walls, but is mainly tcL.fee . ascribed to a reflex stimulation of the _vaso-dilator centre induced by the contraction of the abdominal ves- sels. The brain vessels react in the same way as those of the limbs, digitoxin contracting them, while under strophanthin they are little aifected. The result is that while the outflow from all the vessel's is retarded by digitoxin, the blood current in the splanchnic area alone is slower under strophanthin, while that in the limbs and brain is actually accelerated. The rate of flow through the qpronary vessels of the heart under the members of this series has been investigated by Loeb, who finds that digitoxin contracts these vessels and retards the blood supply of the heart, while s^oj^anthin_a^ have ittle influence on them. 448 ORGANIC DRUGS ACTING AFTER ABSORPTION. It follows that under all of the series the blood tends to accumulate on the arterial side at the expense of the venous, for more blood is pumped into the arteries and it has greater difficulty in escaping. But while under digitoxin the different regions of the body appear to be equally affected, strophanthin, digitalin and convallamarin not only tend to accumulate the blood on the arterial side, but divert it from the internal organs to the limbs. When the extreme slowing of the second stage appears, the output of the heart is reduced, and the pressure in the aorta and the velocity of the blood may become subnormal (Fig. 44). When the acceleration of the third stage follows, the output is again augmented and may be greater than ever ; the blood-pressure and velocity increase, but the heart soon becomes irregular in the force of its contractions, the output varies FIG, 44, /l/WWWWVWWl WV1MA%1/1 ABODE Blood-pressure tracing under digitalis. A, normal ; B, therapeutic stage; C, excessive inhibition causing a low blood-pressure from lessened output of the heart. D, excessive inhibition with some irregularity in rhythm. E, third stage of irregularity, during which the blood-pressure rises again from the increased output of the heart and the further contraction of the vessels. from second to second, and the pressure and velocity in the aorta fall slowly. The blood-pressure tracing shows the irregularity of the heart more or less accurately, but must not be taken to indicate at all the real condition of that organ, as the constriction of the arterioles varies at different times. Eventually the pressure falls to zero, when the heart ceases. In the pulmonary circulation the pressure is not raised by some of the series, such as strophanthin and helleborein, while after digitalis a rise in the pressure in the pulmonary artery is sometimes seen. Yet all of them increase the output of the right ventricle. The explana- tion of this paradox probably is that the pulmonary vessels can con- tain not only the ordinary supply of blood, but also an increased volume without offering any great resistance. In the later stages the pulmonary circulation presents irregularities similar to those of the systemic. THE DIGITALIS SERIES. 449 Action on the Renal Secretion. When digitalis was first introduced to the notice of the medical profession by Withering its action on the heart was not appreciated. Withering used it only to remove accumu- lations of fluid from the body, which it accomplished by increasing the secretion of urine. This observation of Withering was soon confirmed by further experience in the use of this drug, but it was long dis- puted whether this diuretic action occurred in health, or whether it was not confined to cases in which pathological accumulations of fluid were present. Digitalis, however, as is now conceded by almost everyone, causes some increase in the quantity of urine secreted by the normal animal, although this is small compared with that in cases of dropsy. The fluid of the urine is much more largely augmented than the solids, which may remain unchanged. The cause of this increase FIG. 45. A B D D D" Diagram representing the secretion of urine in a rabbit under digitalis. Each rectangle represents the amount of urine secreted in ten minutes. A and B, normal secretion. In the next ten minutes a small dose of digitalis D was injected intravenously and a rapid increase in the secretion followed. At D' and D" further injections were made, each being succeeded by a considerably augmented now of urine. The dotted line represents the average blood-pressure at each period. It will be ob- served that each injection is followed by some increase in the arterial tension. Contrast Fig. 23 (p. 250) as to the amount of the secretion, and also as to the behavior of the blood-pressure. in the renal secretion is not generally believed to be a direct action on the secretory mechanism, such as is met with under caffeine ; on the contrary, the kidneys themselves are supposed to be acted on only in- directly through the changes in the circulation. The renal vessels are contracted by the members of this series in the same way as the vessels of the other abdominal organs (Gottlieb and Magnus), and this might be expected to lessen the secretion of urine, for other agencies which con- tract the renal vessels have this effect. The diuresis induced by digi- talis-must accordingly be ascribed to the cardiac changes and not to the vaso-constrictor action. It may be supposed that the accumulation of the blood in the arteries and the consequent fall of the venous pres- sure, which has been shown to occur, lead to an augmented flow of the lymph into the blood vessels, and that the blood is thus diluted and 29 450 ORGANIC DRUGS ACTING AFTER ABSORPTION. the kidneys therefore incited to abnormal activity, while at the same time their nutrition is improved ; and in addition, the increased pressure in the glomerulus must accelerate the filtration through the capsule. It is possible, also, that at any rate some of the members of this series act as slight irritants to the renal epithelium. The appearance of blood and albumin in the urine of animals after large doses of squills and digitalis certainly indicates some local action quite apart from the cir- culatory changes. The changes in the circulation in man can be followed only imper- fectly. The heart rhythm is very distinctly slower, and the apex beat is much stronger than before the administration of the drug ; the pulse is slower and stronger and the artery feels more tense. It must be added that the strength of the pulse is not to be regarded as a gauge of the changes in the cardiac muscle, for it is due not only to the in- creased strength of the cardiac contraction but also to its slow rhythm. When the heart is beating rapidly, the arteries have no time to empty themselves completely, and the pulse is small, while on the other hand, when digitalis slows the heart, the arteries have time to empty their contents into the capillaries before the next contraction occurs, the walls therefore become more flaccid, and a new wave of blood causes a more distinct impulse. In some cases of fever the vagus seems to have less control over the heart than usual, and after digi- talis there is no very marked slowing, although the action on the car- diac muscle may be fully developed. The pulse is harder owing to the increased blood-pressure, but it is not much slower, and the im- pulse does not seem stronger than before. If the physician, judging from the pulse that the drug has been given in too small quantities, prescribes larger doses, the eifects on the heart may be disastrous, as the third stage of irregularity and less perfect action of the heart may be induced. In those cases in which this series seems to have no action on the pulse, the heart and the general condition of the circulation must be very carefully examined before larger quantities are prescribed. If, for example, the urine be found increased, or the oedema is less marked than before, or the breathlessness and the dyspnoea have dis- appeared, the drug is fulfilling its chief purpose, even though the pulse remains apparently unchanged. In Cases of Poisoning with the digitalis series, the most alarming symptoms arise from the circulatory changes. In the well-known case of Koppe, who accidentally poisoned himself in the course of his investigations on digitoxin, the first symptoms were uneasiness, giddi- ness, nausea and vomiting, and great muscular weakness. The pulse then fell to about half its normal rate and became intermittent, and the increasing muscular weakness was accompanied by precordial anxiety, imperfect vision, and constant nausea and vomiting, which prevented sleep and rest, and which persisted for over thirty-six hours without improvement. The symptoms then slowly disappeared and he recovered entirely in about a week. The quantity taken by him was 2 mg. (^L- gr.) ; but four days previously he had taken 1 mg. (^ gr.), THE DIGITALIS SERIES. 451 and it is possible that this may not have been absorbed completely. In any case the small dose of digitoxin necessary to induce almost fatal symptoms indicates that it is one of the most powerful poisons known at present. The main action of this series is on the circulation, but some other results of their administration of less consequence have been observed. Thus in fever the Temperature is not infrequently reduced, although it remains unchanged after the administration of digitalis to the normal animal. This action is said by some to be the result of collapse, while others believe it to be due to the changes in the circulation, but neither of these seems to be a very happy explanation. It has been stated already that the members of this series act as stimulants to some parts of the central nervous system, and a possible explanation of their antipyretic action would be an increased activity of the temper- ature-controlling centre. It has been shown by Harnack that several central nervous stimulants, including picrotoxin, cause a fall in the temperature in this way. Another observation which has been made in regard to this series is that it tends to weaken and eventually to paralyze the Muscles, and still more, the terminations of the peripheral Nerves of the frog. For this purpose it has to be applied in quantities which would at once stop the mammalian heart, and this action certainly never even commences in warm-blooded an- imals. Large quantities of digitalis are said to act on the unstriated muscle of several organs, such as the stomach and uterus, and to increase their movements. PREPARATIONS. Digitalis (U. S. P.), Digitalis Folia (B. P.), foxglove, the leaves of Digitalis purpurea collected from plants of the second year's growth. 0.03-0.1 G. (i-2grs.). Extractum Digitalis (U. S. P.), 10-20 mgs. (-i gr.). Fluidextractum Digitalis (U. S. P.), 0.05-0.1 c.c. (1-2 mins.). INFUSUM DIGITALIS, IT. S. P.", 4-8 c.c. (1-2 fl. dr.); B. P., 2-4 fl. drs. TINCTURA DIGITALIS (U. S. P., B. P.), 0.3-1 c.c. (5-15 mins.). " Digitaline " of commerce varies much in composition and in dose, some- times proving entirely inert, while at other times it has proved poisonous in comparatively small quantities. Crystalline digitaline very often consists largely of digitonin, which is entirely devoid of the digitalin action. Other preparations seem to contain much digitophyllin. " Digitalinum verum" is said to be pure digitalin, and may be injected subcutaneously without dan- ger. 2-6 mg. GWo gr.). Digitoxin has been prescribed in doses of T V mg. (y^ gr.), but the forms at present on the market vary greatly in strength. The tincture and infusion are the most commonly used preparations. The extract and the powdered leaves may be given in the form of pills. The preparations ought to be freshly made, and solutions of ' ' digitaline ' ' and digi- toxin must not be kept, as they soon decompose and become entirely inert. Strophanthus (U. S. P.), the seeds of Strophanthus hispidus. Strophanthi Semina (B. P.), the seeds of Strophanthus Kombe. Extractum Strophanthi (B. P.), \-\ gr. TINCTURA STROPHANTHI (U. S. P., B. P.), 0.3-1.0 c.c. (5-15 mins.). Strophanthinum (U. S. P.), varies in composition and in power. Its dose is gen- erally given as 1 mg. (^ gr.), but this is often devoid of action, while in other cases 0. 2 mg. has been found a sufficient dose, and it is therefore to be used with 452 ORGANIC DRUGS ACTING AFTER ABSORPTION. caution. Its solutions are very liable to decompose and have to be freshly pre- pared. Scilla (U. S. P., B. P.), squills, the bulb of Urginea maritima, Urginea Scilla, or Scilla maritima, deprived of its dry membranaceous outer scales and cut into thin slices. 0.05-0.2 G. (1-3 grs.) in pills. Acetum Scillce (U. S. P., B. P.), 1-2 c.c. (15-30 mins.). Fluidextractum Scillce (U. S. P.), 0.05-0.1 c.c. (1-2 mins.). TINCTURA SCILLA (U. S. P., B. P.), 0.3-1 c.c. (5-15 mins.). SYRUPUS SCILLA (U. S. P., B. P.), 2-4 c.c. (30-60 mins.). SYRUPUS SCILLCE COMPOSITUS (U. S. P.), containing senega and tartar emetic, 0.5-2 c.c. (10-30 mins.). Oxymel Scillse (B. P.), $-1 fl. dr. Pilula Scillse Composita (B. P.), contains ginger and ammoniacum, 4-8 grs. PILTJLA IPECACUANHA CUM SCILLA (B. P.), contains 5 per cent, opium. 4-8 grs. Squills is often prescribed in pill form as a diuretic ; as an expectorant the syrup is more often used. The compound syrup, U. S. P., or the pill of Ipecac and Squill, B. P., may be ordered instead of a cough mixture, as they contain the chief constituents of such remedies. Scillitoxin, etc., of commerce are merely purified extracts and not pure principles. Apocynum (U. S. P.), Canadian hemp, the root of Apocynum cannabi- iium. Fluidextractum Apocyni (U. S. P.), 0.3-1 c.c. (5-15 mins.). Convallaria (U. S. P.), Lily of the Valley, the rhizome and roots of Con- vallaria majalis. Fluidextractum Convallarice (U. S. P.), 0.3-1 c.c. (5-15 mins.). Euonymus (U. S. P.), Euonymi Cortex (B. P.), Wahoo, the bark of the roots of Euonymus atropurpureus. Extractum Euonymi (U. S. P.), 0.05-0.2 G. (1-3 grs.). Extractum Euonymi Siccum (B. P.), 1-2 grs. Therapeutic Uses. The chief purpose for which this series is used in therapeutics is to counteract certain changes in the circulation, which result in the blood accumulating in the veins in too large quantities, while the arteries are less completely filled than usual. And first of all, in cases of dilatation of the heart with a weak and insufficient systole, its action is almost specific. This is true whether one or both ventricular chambers are affected, as long as the cardiac muscle itself has not undergone degeneration. In these cases the action is very simple the increased ventricular systole approaches the normal, the output of the heart is increased, and in some cases at any rate, the dilatation is diminished by the direct action of the drug. The effect is an increased velocity and pressure in the arteries, and an improved nutrition of the whole body. The organ which suffers most of all under the malnutrition caused by dilatation of the chambers is the heart itself, and, accordingly, in these cases the heart is found better nourished and has more tendency to hypertrophy after digitalis or its allies. Eventually the walls of the heart become so enlarged as to be able to carry on the work without the additional stimulation of digitalis, and the drug ought therefore to be stopped. It must be remembered that the hypertrophy of the heart is not a direct effect of this series, which only puts the organ in a condition in which it receives more nourish- THE DIGITALIS SERIES. 453 ment and is therefore more likely to hypertrophy. The effects in these cases of dilatation seem to be attributable entirely to the action on the cardiac muscle. It is frequently stated that the slowing of the heart, which allows the heart more time to rest and more time to fill itself, is accountable for the improve- ment. But numerous other drugs slow the heart quite as much and in exactly the same way, yet are of no benefit but rather the reverse in those condi- tions in which digitalis is most valuable. Aconitine, for example, slows the heart by stimulating the vagus centre, but no one would dream of using aconite as a substitute for digitalis in dilatation of the ventricles. Another explanation of the action of digitalis in cardiac dilatation is that the vagus being the trophic nerve of the heart, its stimulation increases the tendency of the heart to hypertrophy, and this series therefore causes hyper- trophy by stimulation of the trophic nerve. Any explanation which requires the assumption of trophic nerves is fraught with danger, however, and this one is easily refuted by the fact that aconite does not induce hypertrophy of the heart. The true explanation of the action of digitalis is the action on the cardiac muscle, by which the systole is strengthened and the output of the heart is increased. Mitral incompetency may be taken as a concrete example of cardiac disease. Here some of the blood, instead of passing into the aorta during the ventricular systole, passes back into the auricle. In course of time the auricle dilates owing to the pressure during its diastole, and the consequence is that the lungs become congested, the right ventricle and eventually the right auricle dilate, and the whole systemic circulation is retarded. (Edema and dropsy follow, the kidneys and other organs become overfilled with blood, and the whole economy is thrown into disorder. The left ventricle is not affected directly by the pressure, but it suffers in the general malnutrition, and may become weak and dilated like the rest of the heart. If now one of this series be given, the right and left ventricles commence to beat more strongly, their out- put is increased, and the blood is forced through the lungs. It still regurgitates into the left auricle, but the proportion passing back to that driven forward is smaller, owing to the increase in systole, which lessens the mitral orifice. Moreover the right ventricle is able to over- come the pressure in the pulmonary artery, and therefore soon ceases to drive blood into the right auricle, and the systemic veins can pass their blood into the heart without difficulty. The congestion of the organs rapidly disappears, the kidneys become better nourished, and finding large quantities of fluid accumulated in the body, at once proceed to excrete it. The heart itself improves in condition, but more work is required of it than in the normal body, because some of its work is still lost through the blood passing backwards from the ventricle in- stead of forwards. The muscle responds to the strain by hypertrophy, and when this process is complete, the drugs have fulfilled their pur- pose, and further administration is useless and may be dangerous. The only action of the drug required here is the increased contraction of the ventricles and auricles in systole, and this is exactly the point 454 ORGANIC DRUGS ACTING AFTER ABSORPTION. in which this series differs from all others. At the same time, if the diastolic dilatation becomes less marked, as it does in many experi- ments on the normal heart, this must also aid in such a case, because the more dilated the ventricle, the less perfectly does the mitral valve close the auriculo-ventricular orifice at the beginning of systole. If then the dilatation of the heart becomes less, either from a direct action of the drug, or as a result of the improved nutrition of the muscle, the imperfection of the valve may be compensated for by the narrowing of the orifice. If the muscular action predominates sufficiently over the inhibitory, a further factor may aid in repairing the breach of the valve, for the auricular muscle is acted on in the same way as the ventricu- lar its contraction is more complete, and the auricle therefore emp- ties itself more perfectly, and contains less blood at the beginning of the ventricular systole than it otherwise would. If, in addition, the auricular relaxation is lessened by digitalis, a greater resistance must be offered to the regurgitating blood. The increased contraction of the papillary muscles may also aid in the therapeutic effect by closing the valves more completely. In aortic incompetency the same beneficial results may be expected, because here again there is more blood expelled into the aorta, and at a higher pressure. The less dilated ventricle also presents a greater resistance to the return of the blood. It is true that longer time is allowed for the blood to pass back into the ventricle owing to the pro- longation of the diastolic pause, but this does not seem to be sufficient to counterbalance the benefits of the more complete contraction of the ventricle. In narrowing of the orifices, the improvement observed after digi- talis may also be explained by the stronger and more complete con- traction of the ventricles. Stenosis very rarely occurs unaccompanied by regurgitation, however, and the diminution of the backward flow may be the main object attained by these drugs in this condition. On the right side of the heart the same action occurs as on the left, and in dilatation of the right ventricle, which often occurs as the result of pulmonary disease, this series acts by increasing the strength of the ventricular contraction. In numerous acute febrile conditions the heart becomes affected, possibly in part by the high temperature, but largely from the toxic products circulating in the blood. The chief cardiac symptoms are dilatation with a weak systole and a small "fluttering" pulse. In these cases digitalis and other similar drugs may be of great service in slowing the accelerated heart and in increasing the extent of systole, and thus improving the general circulation. In pneumonia more especially, great improvement is often seen after digitalis. In this disease, besides the toxic action on the heart there may be present more or less obstruction of the pulmonary vessels through pressure, resulting in overwork and dilatation of the right heart. The routine treatment of pneumonia with digitalis is often recommended, but is to be deprecated on the general principle that a drug is not to be pre- THE DIGITALIS SERIES. 455 scribed until some special indication for it appears ; unless distinct evidence of circulatory disturbance is present, digitalis ought to be withheld. In acute fevers the inhibitory mechanism is often less irritable than normally, and the activity of the drug must not be estimated by the slowness of the pulse. (See page 450.) In some forms of dilatation of the heart digitalis and its allies are to be avoided. Thus where extensive degeneration of the heart mus- cle is present, as in fatty heart, little or no benefit from the muscular action is to be expected, for the muscle itself is too weak to respond to the stimulation. On the other hand, digitalis, by increasing the pressure against which the heart has to contract, may cause the most serious re- sults the systole becomes even weaker than before its administration, and brain anaemia, syncope, and not infrequently sudden death follow. In other cases, while the condition of the heart is eminently suitable for digitalis treatment, disease of other parts of the body may preclude its use. Thus if extensive degeneration of the arterial coats is present, the increased pressure in the interior of the vessels may lead to rupture of their walls and apoplexy. In those cases, if any of the series is to be given, it ought to be strophanthus, which causes a less extensive rise in the blood-pressure than digitalis, and it is recommended that either be prescribed along with some drug to dilate the vessels and lessen the arterial tension, such as nitroglycerin or some other of the nitrite series. In treating with digitalis and a member of the nitrite series, it is found that the digitalis action sets in somewhat slowly, and persists for a long time, while the nitrites act rapidly, but are excreted com- paratively soon. The best results are therefore obtained by frequent small doses of nitroglycerin, which need not be administered for some hours after the first dose of digitalis. In some cases dilatation of the heart seems to be due, at any rate in part, to increased arterial tension from disease of the arterial walls and of the kidneys. In these cases digitalis is to be used with caution, because of its vaso-constrictor action, and perhaps strophanthus is to be preferred to digitalis, unless one of the nitrite series is associated with the latter. Valvular disease is not in itself an indication for digitalis, for the heart tends to undergo compensatory hypertrophy in favorable condi- tions without the use of any drug whatever, and digitalis is indicated only when no such compensation occurs. At the same time hyper- trophy of the heart is not a centra-indication, as is often stated, for a special strain may cause excessive dilatation in a hypertrophied heart, and digitalis may be necessary until a second hypertrophy has occurred and restored the equilibrium once more. Digitalis is often prescribed in tachycardia (rapid heart) in order to slow the rhythm only, but if no other symptoms than acceleration are present, other drugs, such as aconite or strychnine, may be substituted for digitalis, and do not entail the other changes in the circulation. It has been mentioned that the exhibition of digitalis in fever is 456 ORGANIC DRUGS ACTING AFTER ABSORPTION. often followed by a fall of temperature, and Traube recommended it as an antipyretic, but it is no longer used for this purpose, as the modern antipyretics are much more powerful and certain in their action, and at the same time are less dangerous. The diuretic action of digitalis is also not advised except where other indications than a diminution of the renal secretion are present, for in ordinary cases it has much less effect than caffeine and other diuretics. If the anuria be secondary to disturbances of the circula- tion, however, digitalis is the diuretic par excellence and cannot be replaced by any of the ordinary means of promoting the urinary secre- tion, although they may advantageously be combined with it. Squills is more frequently used as a diuretic than digitalis, and it seems prob- able that in addition to its action on the heart and circulation, it exer- cises some direct stimulant influence on the renal epithelium. Squills and digitalis are often prescribed together, where large accumulations of fluid have to be removed. A famous pill used in these cases con- tains a grain each of digitalis, squills and calomel. Several of these drugs are of considerable benefit in pulmonary diseases accompanied by cough. Thus in bronchitis, more especially in cases of old standing, the addition of squills to an " expectorant mixture" is often followed by the most satisfactory results. The action here is probably two-fold. In the first place, the right heart may be dilated owing to the frequent strain put on it by coughing, and squills remedies this condition by its usual cardiac action. In the second place, all these drugs possess to a certain extent emetic prop- erties, and thus cause an increase in the bronchial secretion, and ren- der the sputum less tenacious and more easily expectorated. The addition of squills, in which this property is more developed than in the others, has the same effect as the prescription of ipecacuanha, along with the further action on the heart. Digitalis is sometimes prescribed to stop haemorrhages, but though it constricts the vessels it accelerates the flow through them, and, as in the case of other haemostatics, the benefits arising from the treatment are problematical. In the circulatory weakness following severe hem- orrhage and shock the effects of this series would seem to be indi- cated, were it possible to elicit their action sufficiently rapidly. Unfor- tunately many hours generally elapse before the heart and vessels are affected, when they are exhibited by the mouth. These conditions are generally treated by more rapidly acting measures, such as the intra- venous injection of salt solution ; the effects of this treatment are maintained much longer if a small quantity of digitalis tincture is added to the salt solution. Squills was at one time used as an emetic, but this cannot be recom- mended, owing to the danger of its absorption. Euonymus has been employed as a purgative more frequently than as a cardiac remedy. (See page 107.) Some conditions in which the cardiac action of this series is to be elicited only with the greatest caution, have been already indicated. THE DIGITALIS SERIES. 457 A further danger, which attends the use of digitalis perhaps more than that of the rest of the series, is due to its Cumulative Action. For the first day or two after the exhibition of this drug no effects may be noted in the pulse or general circulation ; the ordinary symp- toms are then produced, and if the drug be continued, remain fairly constant for some time. Sometimes much more marked symptoms of digitalis action appear suddenly, however, the pulse becomes alarm- ingly slow and irregular, the patient complains of weakness and faint- ness, nausea and occasionally vomiting, in fact the symptoms of the second stage set in. This is known as cumulative action, and is prob- ably due to irregularities in the absorption and excretion or destruction of the poison. It is known that the absorption is slow, for 1236 hours may elapse before any effects follow the exhibition of the drug. On the other hand, the excretion or destruction must be equally slow, for the symptoms sometimes last for several days after it has been dis- continued. If then anything happens to disturb the equilibrium of absorption and excretion, if, for example, the excretion is slower than usual, or if any irritation of the stomach and intestines causes a more rapid absorption, the drug accumulates in the blood, and the same effect is produced as if a poisonous dose had been administered. In order to avoid this cumulative effect, the condition of the pulse must be carefully controlled, and as soon as the circulation shows any signs of excessive action, the drug ought to be discontinued for one or two days and resumed in smaller quantities. These cases of poisoning are not serious if observed in time. All of the digitalis series hitherto examined prove to be cumulative in their action, but some of them, notably digitoxin, are much more dangerous than others. In fact, according to Fraenkel, digitoxin can only be used safely in doses which induce no changes in the pulse for several days, for if the pulse be slowed by a single dose, its repetition within twenty-four hours induces severe poisoning. Another disagreeable feature observed in the use of this series is the action on the stomach and intestine. As has been noted already, the local action may produce the usual symptoms of gastric irritability, and the patient suffers from loss of appetite, nausea and gastric dis- comfort, just when it is important that the nutrition should be the best attainable. Numerous attempts have therefore been made to obtain preparations which possess the cardiac without the local action. Some of these seem to be fairly free from irritant properties ; for example, some of the digitalines can even be injected subcutaneously without giving rise to any irritation or inflammation. But unfortunately all those preparations vary so much in strength, even when prepared by the same method, that their use is scarcely to be recommended. At the same time, in cases where the ordinary pharmacopoeial preparations cause marked gastric irritation, some of the so-called " pure principles " may be made use of with advantage. So little is known regarding the comparative action of the members of this series that the special indications for each individual are alto- 458 ORGANIC DRUGS ACTING AFTER ABSORPTION gether indefinite. It is recognized that strophanthus acts less on the vessels than digitalis, and this gives an indication for its use in some cases. On the other hand, squills acts more on the kidneys than either, and is therefore given frequently as an adjuvant to digitalis in cases where diuresis is desired. It also irritates the gastric mucous mem- brane more, and is often used as an expectorant. But the details of the action of each are still to be worked out. One important question, which is practically unbroken ground, is the relative action of each on the vagus centre and on the heart. The beneficial results from the use of digitalis are, as has been pointed out already, to be ascribed almost entirely to its action on the cardiac muscle. The stimulation of the vagus may conceivably lessen the benefits of the cardiac action by weakening the auricular contraction and slowing the rhythm, so that it would be of considerable interest and importance to find a drug having the same cardiac action without the inhibitory, 1 and, failing in this, to compare the eifects of digitalis alone with those of digitalis and a drug which weakens the inhibitory action. This would have to be given in quantities sufficient to prevent an increased inhibition without cutting off the normal restraining impulses which pass down the vagi, and the treatment would be rendered considerably more difficult. BIBLIOGRAPHY. The bibliography on the digitalis series is so extensive that the student can only be referred to that given by the following authors. Boehm. Pfl tiger's Arch. f. d. ges. Physiol., v., p. 153. Schmiedeberg. Arch. f. exp. Path. u. Pharm., xvi., p. 149. Robert. Ibid., xxii., p. 77. Francois- Franck. Clinique medicale de la Charite. Paris, 1894, p. 549. Cushny. Journ. of Exp. Med., ii., p. 233. Harnack. Berl. klin. Woch., 1895, p. 759. (Erythrophloeine.) Marshall. Journ. of Physiol., xxii., p. 1. Pfaff. Arch. f. exp. Path. u. Pharm., xxxii., p. 1. .Klingenberg. Ibid., xxxiii., p. 353. Goldenberg. Inaug. Diss., Dorpat, 1892. Jarmerstedt. Arch. f. exp. Path. u. Pharm., xi., p. 22. (Scilla.) Cervello. Ibid., xv., p. 235. (Adonis.) Fraser. Trans. Koy. Soc. Edinburgh, 1890 and 1891. (Strophanthus. ) Fraser and Tillie. Arch, internat. de Pharmacodyn., v., p. 349. (Acokanthera. ) Prevost. Trav. du Lab. therapeut. exp., ii., p. 221. Lewin. Virchow's Arch., cxxxiv., p. 231 ; cxxxvi., p. 83; cxxxviii., p. 283. Kiliani. Arch, der Pharmacie, 1892-1899. Hedbom. Skandin. Arch. f. Phys., viii., p. 185. Arch. f. exp. Path., xlv., p. 317. Fraenkel. Arch. f. exp. Path. u. Pharm., xl, p. 40 ; Ii., p. 84. Resh. Ibid., xliii., p. 130. . Straub. Ibid., xlv., p. 317. Cloetta. Ibid., xlv., p. 435. Gottlieb, Sahli, etc. Verhandl. d. Congress f. inn. Med., 1901. Wybauw. Arch. f. exp. Path. u. Pharm., xliv., p. 434. Braun u. Mager. Sitzungsb. d. Wiener Akad. Math, naturwissen. Cl., cviii., iii., p. 471. Faust. Ueber Bufonin u. Bufotalin, Leipsig, 1902 ; Arch. f. exp. Path. u. Pharm., xlix., p. 1. Gottlieb and Magnus. Arch. f. exp. Path. u. Pharm., xlvii., p. 135; xlviii., p. 262; Ii., p. 30. Faust. Ibid., xlviii., p. 272. (Acocantherin.) Loeb. Ibid., Ii., p. 64. 1 Helleborein has comparatively little action on the inhibition, but in a number of cases of cardiac disease in which I have attempted to substitute it for digitalis it induced irritation of the intestine and diarrhoea through its local irritant action. SUPRARENAL OR ADRENAL GLANDS. 459 XXIX. SUPRARENAL OR ADRENAL GLANDS. The suprarenal capsules of animals have recently been shown to contain a body which possesses a powerful action on the organism, and which the glands normally secrete into the blood vessels. The active principle, which seems to be rather unstable, has been isolated in two forms Epinephrine (Abel) and Adrenaline (Takamine and Aldrich) or Suprarenine (Fiirth). Some chemical differences exist between epinephrine and adrenaline, but they are very nearly related, and the one appears to be readily changed to the other by simple chemical manipulations ; each elicits the characteristic effects in living tissues, and each molecule appears to contain a dioxybenzol radicle. FIG. 46. Tracing of the blood-pressure under the influence of extract of suprarenal gland, which was in- jected into the jugular vein at a. In the frog, the suprarenal extract causes paralysis of the central nervous system, which is of only short duration, however, even when large quantities are injected. In mammals the hypodermic application of large doses is followed, as a general rule, by some excitement, agita- tion, and often tremors, although these are not marked in the rabbit ; vomiting has frequently been observed in dogs. This stage is fol- lowed by paresis of the hind limbs, often by rapid respiration and dyspnoea, and eventually by failure of the respiration and death. In some animals the urine is increased in quantity, and haemorrhages occur from the mucous membranes and from the kidney. It is to be noted that only large quantities of the gland are fatal when they are injected hypodermically, and it may be doubted whether any symptoms can be produced when it is absorbed from the stomach and intestines. On the other hand, comparatively small quantities elicit marked symptoms when they are injected into the blood vessels, these consist- ing in a very rapid and very pronounced rise of the blood-pressure, with slowing and strengthening of the heart beat. The action of the 460 ORGANIC DRUGS ACTING AFTER ABSORPTION. suprarenal extract injected into a vein is in short that of the members of the digitalis series. The slowness of the pulse is due to stimulation of the pneumogastric centre in the medulla oblongata, while the heart muscle is affected in the same way as by digitalis, that is, its systole is much strengthened and its diastole is often rendered less complete. The rise in the blood-pressure is due chiefly to a marked contraction of the peripheral arterioles from direct action on the muscular coats, in part to the increased efficiency of the cardiac contractions, perhaps in part to stimulation of the vaso-motor centre. The extract differs from the digitalis series chiefly in the rapidity with which these changes are elicited, in the rise of blood-pressure being greater, and in the action passing off more quickly. Mere traces of epinephrine are sufficient to cause this change in the blood-pressure when they are injected intravenously, while no distinct effect is pro- duced by much larger quantities injected subcutaneously or adminis- tered by the mouth. Large quantities of the extract injected into a vein cause the same form of irregularity as the members of the digitalis series, and in one case fibrillary contraction of the heart has been observed from it. The frog's heart seems to be acted on less by suprarenal extract than the mammals', but Oliver and Schafer observed changes in it- similar to those induced by digitalis. Some of the vessels do not seem to be influenced by it so much as others ; thus the pulmonary vessels are not narrowed at all or only very slightly, and even the direct application of the extract to the lungs does not cause pallor. The cerebral vessels also seem to undergo no constriction and in fact some evidence of their dilatation is pre- sented by the widening of the retinal vessels. This is due to the con- striction of the vessels in other parts of the body which diverts to the brain a larger amount of blood than usual. Gerhardt states that the vessels of muscle are scarcely changed in calibre, while those of the skin are contracted, but not in so marked degree as those of the abdom- inal organs. The constriction of the vessels of the stomach, intestine and other organs whose blood flow is regulated by the splanchnic nerve, is apparently the chief factor in the rise of blood-pressure, although the action is by no means confined to these. Even neighbor- ing organs vary considerably in their reactions ; for example, the uterine vessels are constricted while those of the bladder are much less affected. The contraction of the vessel walls may be demonstrated by perfus- ing blood containing epinephrine or the gland extract through the artery of an excised organ, for very much less blood escapes from the vein than when pure blood is used. Or a solution of the extract may be applied to the exposed mesentery, when the vessels are often entirely obliterated. The mucous membranes are similarly affected as is well seen in irritation of the conjunctiva, for the redness and congestion give place to pallor when epinephrine solution is applied. It has no SUPRARENAL OR ADRENAL GLANDS. 461 effect on the unbroken skin, through which it is unable to penetrate to the vessels, but denuded surfaces become pale and anaemic under its influence and haemorrhages cease from the smaller vessels and capil- laries. In addition to the vessels a number of other forms of unstriated muscle are thrown into a condition of spasmodic contraction by supra- renal extract. Thus the muscular fibres of the eye that are innervated from the superior cervical ganglion undergo contraction when the drug is injected intravenously or applied locally. This results in dilatation of the pupil, withdrawal of the nictitating membrane, separation of the eyelids and protrusion of the eyeball, exactly as after cocaine or stimu- lation of the cervical sympathetic. The muscle fibres supplied by the third nerve are unaffected. The contraction of some involuntary muscles is inhibited by suprarenal extract, so that the cardiac sphincter of the stomach and the internal anal sphincter relax, and the move- ments of the stomach, intestine and bladder are retarded or altogether arrested. The uterus, vagina, vas deferens, seminal vesicles, and the external genital organs are all contracted and anaemic in contrast to the relaxed condition of the stomach and intestine. Adrenalin thus acts on a large number of forms of involuntary muscle and apparently in diametrically opposite ways, causing con- striction in many cases, but inhibiting it in others. It is noted that stimulation of the sympathetic nerves has similar results in most cases ; for example, stimulation of the splanchnic nerves contracts the intes- tinal vessels, but relaxes the muscular coats of the bowel. Many observers have therefore ascribed the effects of suprarenal extract to its stimulating the terminations of the nerves and not to its acting on the muscle fibres directly. The objection is raised, however, that the action persists after degeneration of the nerve-endings, and this seems to indicate that the drug acts on the muscle fibres and that the differ- ence in the results depends on fundamental differences in the chemical characters of these fibres. The secretions of the salivary glands and of the mucous glands of the mouth and throat are increased, apparently through stimulation of the nerve terminations, as under pilocarpine. The secretion is arrested by atropine, but can be reinstated by larger amounts of suprarenal extract, which is a more powerful antagonist to atropine than pilocar- pine. The lachrymal glands and the bile are also increased, while the secretion of the pancreatic juice and of the sweat is probably unchanged. Suprarenal gland extract injected hypodermically or intraperito- neally causes glycosuria from an excessive formation of sugar in the liver ; this appears to be due not to direct action on the liver, but to a secondary effect from the pancreas, for adrenaline applied directly to the latter has the same effect. The action of adrenaline on the blood vessels is of very short duration, and this has been ascribed to its being rapidly excreted or 462 ORGANIC DRUGS ACTING AFTER ABSORPTION. oxidized ; recent experiments have shown that neither of these expla- nations suffices, for if the circulation is shut off from a limb before the injection of adrenaline into the general circulation, and the ligature is removed only after the effects on the other tissues have passed off, the vessels of the previously occluded limb contract vigorously ; this indi- cates that enough of the drug is still present in the blood to contract fresh unpoisoned vessels, although those at first affected no longer respond to it. Preparations. Extracts were at first made from the fresh glands, but soon the dried glands were introduced glandules suprarenales siccce (U. S. P.), the dried glands of the sheep or ox and a watery solution made from these may be used. The active principle has been put on the market under the name of ADRENALINE, and this has almost entirely supplanted the cruder preparations. It is generally used in 1 per mille solution, but often in one-tenth or even one-fiftieth of this strength. This solution may be disinfected by boiling, and does not induce any general symptoms unless when injected intravenously and rapidly. Therapeutic Uses. Disease of the suprarenal gland leads to a series of symptoms known as Addison's disease, and it has been supposed that the extract of the gland might counteract this condition by sup- plying the substance whose deficiency induced the symptoms. As a matter of fact, however, but little success has attended its use for this purpose, and the failure may perhaps be due to the method of applica- tion, for it has been shown repeatedly that the characteristic effects of epinephrine cannot be elicited by its administration by the mouth or subcutaneously. It is possible that the extract might prove beneficial if it could be brought into the blood directly but this is quite impos- sible in a chronic condition such as Addison's disease. Its general action on the circulation might be taken advantage of in such emergencies as heart failure under anesthesia or in shock, and in fact Gottlieb has shown that in animals poisoned with chloral or chloroform until the pulse has almost completely ceased, the circulation may be restored immediately by suprarenal extract. In order to elicit this action, the drug would have to be injected intravenously and little danger is to be apprehended from small doses if one can judge from the results in animals ; no such treatment has yet been adopted in man. The great use of suprarenal preparations is however due to its local effects on the vessels. No other body is known which induces such com- plete contraction of the vessels in any part to which it is applied, and in addition suprarenal extract has only local effects, unless injected into the blood. Complete bloodlessness of a part may thus be elicited without alteration of the general blood-pressure, and in fact without any appreciable effect upon other parts of the body. This local ischsemia has been largely employed to allow of bloodless operations on the eye and to remove congestion of the conjunctiva from various causes. It is often administered with cocaine in operations on the eye SUPRARENAL OR ADRENAL GLANDS. 463 (1 in 10,000 solution of adrenaline). In congestion of the nasal mucous membrane and in operations on the nose it is also used exten- sively and with much success ; the 1 per mille solution may be sprayed into the nose, or cotton soaked in it may be packed into the cavity. In epistaxis and in operations on the nose, the haemorrhage ceases almost completely and the contraction of the mucous membrane permits of a clearer view of the field of operation. Hay fever is often relieved by similar treatment with suprarenal preparations. A solution of adrenaline has been found useful in haemorrhage from the ear, mouth and throat, and in controlling haemorrhage in operations in general surgery. Griinbaum first suggested its administration by the mouth in gastric haemorrhage, in which the action is confined to the mucous membrane of the stomach. Similarly it may be injected into the rectum, bladder and uterus in congestion or haemorrhage from these organs, and Schiifer recommends it especially in post-partum haemorrhage, in which it acts not only on the uterine vessels but also on the muscular walls, and arrests the bleeding by causing a tonic contraction. In all of these cases the suprarenal preparation has to be applied directly to the bleeding organ ; and no effects will follow from its being carried to them by the circulation. The local contraction of the vessels lasts very much longer than that induced by intravenous injection, for even dilute solutions induce ischaemia lasting from thirty minutes to two hours, according to the rapidity with which the extract is absorbed. The vessels of some organs do not contract under adrenaline, and no benefit is to be expected from its application in haemorrhage from these ; spraying adrenaline into the lungs in case of haemoptysis, for example, is quite useless, and similarly haemorrhage in operations on the brain cannot be controlled by it. The constriction of the vessels in a part to which adrenaline is applied retards the absorption of poisons injected with the adrenaline, and at the same time permits of their exercising a more marked local effect. This fact has been utilized in surgery to prevent the absorp- tion of cocaine and intensify its local action, and the method has been attended with most encouraging results. A few drops of the 1 per mille solution are added to the Schleich's solution of cocaine, and blanching of the tissues results ; eucaine does not give such a satisfac- tory reaction. BIBLIOGRAPHY. Oliver and Schdfer. Journ. of PhysioL, xviii., p. 230. Brit. Med. Journ., 1901, i., p. 1009. Szymonowkz. Pfliiger's Arch., Ixiv., p. 97. Bates. New York Med. Journ., Ixiii., p. 647. Vincent. Journ. of PhysioL, xxii., pp. Ill and 270. Bardier. Arch, de Phys. (5), x., p. 370. Joum. de PhysioL, -., p. 950. Gottlieb. Arch. f. exp. Path. u. Pharra., xxxviii., p. 99. Abel. Ztschr. f. phvs. Chem., xxviii., p. 318. Johns Hopkins Hospital Bulletin. July, 1897; Nov., 1901*; Feb., 1902. 464 ORGANIC DRUGS ACTING AFTER ABSORPTION. Lewandowsky. Arch. f. [Anat. u.] Phys., 1899, p. 360. Boruttau. Pfliiger's Arch., Ixxviii., p. 97. Gerhardt. Arch. f. exp. Path. u. Pharm., xliv., p. 161. Langley. Journ. of Physiol., xxvii., p. 237. Griinbaum. Brit. Med. Journ., 1900, ii., p. 1307. Amberg. Arch, internat. de Pharmacodyn.. xi., p. 57. Herter and Wakeman. Amer. Journ. Med. Sciences, cxxv., p. 46. Virchow's Arch., clxix., p. 479. Weiss and Harris. Pfl tiger's Arch., ciii., p. 510. Meltzer and Auer. Amer. Journ. of Phys., xi. Brodie and Dixon. Journ. of Physiol., xxx., p. 491. Lowen. Arch. f. exp. Path. u. Pharm., li.. p. 415. Braun. Arch. f. klin. Chir., Ixix. XXX. THE NITRITES. The nitrites would naturally fall among the inorganic salts, but they act chiefly upon the circulation, so that it is convenient to place them near the digitalis series. Those which have been examined more carefully are the Nitrite of Sodium, and the Nitrous Ethers of the methane series, especially the Nitrite of Amyl, which is largely used in therapeutics. In these com- pounds the radicle NO is attached to the metal or alkyl through an atom of oxygen, the formulae being K O NO, CH 3 O NO, C 3 H 7 O NO, C 5 H n O NO, etc., and the chief constituent is the O NO, the metal or radicle being of less importance. A closely allied series of bodies are the nitrates, in which the nitrogen has five affinities and is connected again to the metal or radicle by oxygen, K O N0 2 , CH 3 O N0 2 , C 6 H n O NO 2 , etc. The metallic nitrates differ entirely from the nitrites in their effects and will be dis- cussed along with the other inorganic salts. Some of the Nitric Ethers, however, undergo a reduction when brought into contact with organic matter, and nitrites are thus formed, so that these bodies have effects very similar to those of the true nitrites, and have to be discussed along with them. The best known of such nitrates is the so-called Nitroglycerin, which is really the trinitrate of glycerin, (CH 2 (ONO 2 )- CH(ONO 2 )CH 2 (ONO 2 )), and is broken up by alkalies into a mixture of nitrates and nitrites. The nitrates have practically no action in the small quantities given, so that almost all the effects of nitroglycerin are due to the nitrite formed. 1 Many other organic nitrates also form nitrites in the tissues, but none of them with such rapidity as nitro- glycerin. Two which have been used to some extent in the last few years are solids Erythrol Tetranitrate and Mannitol Hexanitrate. They act much more slowly and for a longer time than nitroglycerin. Another series of bodies which may be mentioned as occasionally acting like nitrites, although more feebly, are the nitro-bodies. In these the nitro- 1 Some doubt has been expressed of late years as to whether this reduction to nitrite really occurs in the tissues, and some grounds exist for the belief that nitroglycerin acts as such (Marshall). THE NITRITES. 465 gen is attached to the alkyl directly, and not through the intervention of an H oxygen atom. Examples of these are Nitromethane, HC NO 2 , and Xitro- H H ethane, CH 3 C NO,. Their action is so feeble as to preclude their use in H therapeutics, and seems due to the NO 2 being split off in the tissues and reduced to nitrites in very small quantity. The best known member of the group is Amyl Nitrite, and its action will first be described, while the points in which the effects of the other members diverge from it will be discussed later. The characteristic results of the absorption of amyl nitrite are dila- tation of the vessels and the formation of methsemoglobin. Symptoms. After the inhalation of a few drops of amyl nitrite, the face becomes flushed, and the patient complains of a feeling of fulness and throbbing in the head. Some headache and confusion is often pre- FIG. 47. A B c Tracing of the blood -pressure in the rabbit under amyl nitrite. From A to B, the blood-pressure is the normal. At B the inhalation was begun and the disturbance of the respiration is reflected in the blood-pressure tracing. Immediately afterwards the blood-pressure begins to fall and continues to do so even after the inhalation ceased at C. Note that the rhythm and strength of the pulse are compar- atively little altered. sent, the pulse is accelerated, and the respiration is somewhat quicker and deeper. The flush is often confined to the face and neck, but some- times spreads over the whole trunk, and passes off in a few minutes, unless the inhalation is continued. If large quantities of the drug be inhaled at once, however, or if the inhalation be continued for some time, a feeling of giddiness, weakness and eventually stupor follow, the pulse becomes slow, while the respiration still remains accelerated, but is shallower and often somewhat irregular ; convulsive movements may occur, but in general large quantities may be taken Avithout actual danger in the human subject. The blood is said to have assumed a dark color in some cases, but this seems to be rare. Action : Circulation. In experiments on animals, the flushing and dilatation of the arterioles of the head is found to be accompanied and followed by a profound, fall in the blood-pressure. The heart is accel- erated at the same time, and seems not to be responsible for the change. The cause, as has been repeatedly demonstrated, is the dilatation of the peripheral vessels, both arterioles and veins widening very consid- erably under the influence of the drii ; the vessels of the abdominal 30 466 ORGANIC DRUGS ACTING AFTER ABSORPTION. organs and the head are more affected than those of the extremities. This widening of the vessels might be produced either by depression of the vaso-constrictor centre, or by depression of the nerve ends and jnuscle of the arterioles and as a matter of fact each of these explana- tions has" '*Gad its 'supporters, "but the latter, is now almost universally held to be the correct one. Stimulation of a constrictor nerve such as the splanchnic still produces some rise in the blood-pressure, so that the nerve terminations seem to be intact, and the jseatof action of amyl .nitrite is therefore held to be the unstriated muscle of the arteries and veins. No satisfactory explanation has been offered for the fact that in the skin only the vessels of the head and neck should be dilated, but other facts seem to indicate that these vessels occupy an exceptional position as regards their in nervation and their reactions to drugs. Darwin was the first to point out that the blush of amyl nitrite corre- sponds in extent with the blush produced by emotion. Even in the frog the arterioles of the tongue are said to dilate more than those of the mesentery and the web after the application of amyl nitrite. The vaso- constrictor centre is often said to be depressed by amyl nitrite, and this may possibly be true, though this central action must be quite in- significant compared with that on the arterial walls, and has never been demonstrated even by the most careful and ingenious methods of experimentation. The direct action on the vessel walls may be easily shown by passing blood into the artery of the amputated extremity of an animal, and measuring the amount coming from the vein. If a few drops of amyl nitrite be added to the perfused blood, the outflow from the vein is greatly increased, although here no nervous mechanism can be concerned. The acceleration of the pulse is more marked in man and the dog than in other animals, and seems due to a depression oTthe inhibitory centre in the medulla omongata, though several authors consider that :^ajfeeble, direct action on the Heart is' alscTpresent'." "TJie^cpronary arteries" of the heart are dilated along witntKose~of other parts of the body. """Large quantities of amyl nitrite slow and weaken the contractions of the heart, owing to a direct depressing action on the muscle. In the frog, the heart is usually slowed from the beginning of the appli- cation. The Respiration is generally accelerated, and at the same time ren- dered deeper by amyl nitrite. Sot infrequently the breath is held at first, owing to a reflex from the nasal mucous membrane, but this is not so marked as in the inhalation of more irritant vapors, such as chloroform or ether. The acceleration seems due to a direct action, on the respiratory centre in the medulla. IfTffer long inhalation the res- piration becomes slower and shallower from depression of the centre, and in animals death occurs from its complete paralysis. The dilata- tion of the systemic arterioles permits the accumulation of blood on the venous side of the circulation, and this in turn leads to the amount of THE NITRITES. 467 FIG. 48. blood in the lungs being augmented ; the walls of the pulmonary ves- sels are scarcely affected by the nitrites directly. The Kidneys are not much affected by this series ; occasionally a slight increase in the urine is observed, at other times a decrease, and after large quantities anuria may occur. The changes are evidently due to the changes in the calibre of the renal vessels. A small quan- tity may widen them when they are too contracted to allow of the maximal secretion, while on the other hand, if the normal calibre is the optimal, a nitrite may lessen the secretion by lowering the general blood-pressure. When large quantities lower the pressure, they in- evitably lead to a lessened activity of the renal epithelium, which may result in complete anuria. Small quantities of amyl nitrite seem to have no action whatsoever on the higher parts of the Central Nervous System. The throbbing in the head and slight confusion are evidently due to the dilatation of the ves- sels, in which the brain circulation is involved as well as that of the rest of the body. The sight is curiously affected in some people, for when a dark object on a white background is looked at, it seems surrounded by a yellow ring and that again by a blue one. In the beginning the medullary centres may be acted on reflexly from irritation of the nasal sensory terminations; the respiration is inhibited, while the blood-pressure may rise and the heart be slowed from reflex action on the inhibitory and vaso-constrictor centres respectively. After- wards, the respiratory centre seems to be stim- ulated, the inhibitory is depressed, while the vaso-motor is practically unaffected. The spinal cord is not acted on in mammals, but is de- pressed in the frog. covery. The whole tracing oc- cupied some six minutes. The After larger quantities convulsions are often rapid fan of pressure is followed ! j i . , , . . by an almost equally rapid re- observea ; these seem to be ot cerebral origin, turn to normal. (CASH&DON- and are probably due to direct action on the nerve cells, and not to the circulatory changes, although some authors attribute them to anaemia of the brain. The Peripheral Nerves and the Muscles are unaffected by the inhala- tion of amyl nitrite, but when the frog's muscles are exposed to the direct action of the vapor, they undergo a slow passive shortening and rigor, and on periodical stimulation the contractions become rapidly weaker, until finally no response is made to the electric shock. In- voluntary muscle is more easily affected than striated fibres, as has been shown by the behavior of the intestine and ureters, but even these seem less readily paralyzed than the muscle of the vessel walls, the de- pression and paralysis of which lead to the fall in the arterial tension, Blood-pressure under amyi ni- 468 ORGANIC DRUGS ACTING AFTER ABSORPTION, as has been already stated. The nerve terminations seem to be un- affected even by very large quantities, so that as long as a contraction of the muscles can be elicited by direct stimulation, it follows also on stimulation of the motor nerve, and the vagus terminations in the heart can transmit impulses as long as the heart continues to beat. The Temperature is somewhat lowered by the nitrite series, owing to the dilatation of the skin vessels, but this fall is very insignificant. Amyl nitrite causes the Blood to assume a dark chocolate color, both in the body and in the test-tube. The color is due not to any compound formed by the nitrites, but to their changing the haemoglo- bin to methsemoglobin and nitric-oxide-hsemoglobin compounds in which the oxygen is attached much more firmly than in oxyhaemoglobin, and which differ from it in the absorption bands seen in the spectrum. This change in the haemoglobin does not entail the destruction of the red corpuscles, and the compounds are eventually reduced by the tissues, although the reduction progresses much more slowly than that of ordi- nary oxy haemoglobin. In man, usually very little of the haemoglobin is thus transformed, and even after large quantities have been inhaled no abnormal coloration of the blood is noticeable, but it has been de- monstrated recently that the alteration of the haemoglobin is the cause of death in some animals, through the blood becoming incapable of carrying oxygen to the tissues. If, however, asphyxia be prevented by the inhalation of oxygen under pressure, the tissues themselves are eventually acted on. The formation of methaemoglobin does not seem to bear any relation to the action of the nitrites on the vessel walls. Excretion. After absorption into the blood, amyl nitrite seems to break up with the formation of nitrites of the alkalies. These undergo partial oxidation and appear in the urine in the form of nitrates and nitrites, but the quantity of these excreted is never equal to the nitrite absorbed, so that it seems probable that some part undergoes still fur- ther change and appears as one of the normal excretions. The amyl disappears, and is probably oxidized completely, although some may appear in the breath. Nitrite of amyl given by the stomach is very much less active than when inhaled, as the nitrous acid is freed by the gastric juice and im- mediately decomposes. When injected subcutaneonsly it acts much more slowly and weakly than when absorbed by the lungs, and gen- erally gives rise to glycosuria and slight diuresis. No satisfactory explanation of this fact has been given, but it is possible that the formation of methsemoglobin may cause partial asphyxiation of the tissues, and thus cause the formation of excess of lactic acid and gly- cosuria. The pharmacopoeial amyl nitrite, with which most of the experi- ments have been performed on which the above description is based, is not a pure substance, but consists of the nitrites of two different amyls a-amyl and /9-amyl along with isobutyl, ethyl, and propyl nitrites. A number of the pure nitrites have been examined by Cash and Dunstan, who find that in general features they resemble each THE NITRITES. 469 other closely. The more unstable the compound, the more rapidly does the fall in blood-pressure occur, while the less easily decomposed compounds are somewhat slower in their action, but cause depression of the blood -pressure for a much longer time. The acceleration of the heart and the extent of the rigor produced in the frog's muscle de- pend also on the rapidity of the disintegration of the nitrite compound, and therefore are parallel to the fall in the blood-pressure. The Nitrites of Potassium and Sodium act very similarly to those of the alkyls. They seem to have a more powerful action on muscular tissue, however, at any rate in the frog, for the muscles are paralyzed before the spinal cord, while after amyl nitrate the reverse is the case. They are administered by the stomach, and therefore act more slowly than amyl nitrite, but their effects last much longer. The gastric juice liberates part of the nitrous acid before absorption can occur, and it is immediately decomposed and often causes some eructation. The nitric acid formed from it may also give rise to irritation of the gastro-in- testinal mucous membrane. The nitrite absorbed is excreted as nitrate FIG. 49. 5 10 20 30 40 50 1 hr. | _ _ , | 2 hrs. t | 2>f hrs. ( A Diagram to illustrate the intensity and duration of the action of the members of the nitrite series. The extent of the fall of pressure is measured along the vertical, the duration along the horizontal line. A, amyl nitrite, ethyl nitrite, etc.; B, nitroglyceriu ; C, sodium nitrite ; I), erythrol tetranitrate. The greatest reduction occurs in A, but it passes off for the most part in 5 minutes and entirely in 20. Nitroglycerin acts more rapidly than the last two, and its effects continue almost as Jong as those of sodium nitrite. Erythrol tetranitrate only exerts its full effect after the action of the others has passed off". (After BRADBURY. ) in the urine, although some of it may remain unoxidized. The metal- lic nitrites do not as a rule cause so much headache and flushing of the face and neck as the alkyl compounds. Nitroglycerin produces the same effects as the other members of this series, but acts much more powerfully than either the metallic or alkyl nitrites. It presents some minor points of difference, as in pro- ducing convulsions in the frog and in some mammals when given in very large quantities, and in causing more severe headache in man. Il is not decomposed in the stomach, but on reaching an alkaline fluid, such as the blood, at once breaks up into glycerin, nitrites and nitrates, in the proportion of two parts of the former salt to one of the latter. Its action commences very soon after its administration, and lasts much longer than that of amyl nitrite. The explanation of its greater activity may be that it is absorbed unchanged, but is then broken up at once, while the metallic nitrites are decomposed in the stomach and much of the nitrous acid is lost. The convulsions are probably due to the whole molecule of nitro- 470 ORGANIC DRUGS ACTING AFTER ABSORPTION. glycerin, which may perhaps be decomposed more slowly in some animals than in others. Nitroglycerin is not wholly broken up in the human body, however, for it has been found in the urine, and the headache which so frequently follows its administration in man, has been ascribed to the undecomposed molecule, and not to the nitrite constituent. It is generally supposed to be extremely poisonous, and is prescribed in exceedingly minute doses, but it has been shown that while very small quantities are sufficient to produce therapeutic effects in man, the toxic dose is enormous in animals. Several other organic nitrates have also been found to reduce the blood-pressure, and to cause the formation of methsemoglobin, but their decomposition proceeds much more slowly than that of nitroglycerin, and they have not been much used in therapeutics. Erythrol tetrani- trate and mannitol hexanitrate act more slowly, and the fall of pres- sure is more gradual, and lasts longer than under any others of the series. PREPARATIONS. AMYL NITRIS (B. P.), AMYLIS NITRIS (U. S. P.), a yellow, very volatile fluid, with a strong, fruity odor, soluble in alcohol and ether, but rapidly decom- posed by water. 2-5 drops are poured on a handkerchief and inhaled. A con- venient preparation is the arnyl nitrite ''pearls," which are thin glass capsules, each containing a dose of the remedy, and one of which is broken in the hand- kerchief when necessary. Arnyl nitrite is liable to decompose when kept long, and ought to be used only when recently prepared. SPIRITUS GLYCERYLIS NITRATIS.(U. S. P.), LIQUOR TRINITRINI (B. P.), is a 1 per cent, alcoholic solution of nitroglycerin. 0.03-0.2 c.c. (-4 mins.). TABELL^: TRINITRINI (B. P.), or nitroglycerin tablets, are formed of choco- late, and contain each T ^ gr. of nitroglycerin. 1-2 tablets. Nitroglycerin is much more liable to decompose in tablets than in the alcoholic solution, and the latter ought to be preferred in therapeutics ; even the alcoholic solution should not be kept too long. Liquor Ethyl Nitritis (B. P.), a solution in alcohol and glycerin of ethyl nitrite (2J-3 per cent.), forming a limpid liquid of apple-like odor and taste. 20-60 mins. Sodii Nitris (U. S. P., B. P.) (NaNO 2 ), 0.05-0.1 G. (1-2 grs.). It may be prescribed in tablets or in solution. SPIRITUS ^ETHERIS NITROSI (U. S. P., B. P.), sweet spirits of nitre, con- tains only traces of ethyl nitrite, along with ether and aldehyde in alcoholic solution. When freshly prepared it acts like the other nitrites, but when prescribed along with water, as is usually the case, the nitrite escapes rapidly, and it has little effect except from the ether and alcohol. 1-5 c.c. (20-90 mins.). Nonofficial. Erythrol tetranitrate (CH 2 ONO 2 (CHONO 2 ) 2 CH 2 ONO 2 ) is a solid, and is recommended in doses of 0.05 G. (1 gr.), in pills, tablets or alcoholic solu- tion. Like nitroglycerin, it is a dangerous explosive, and one fatality has already occurred in forming it into pharmaceutical preparations. Therapeutic Uses. The nitrites were introduced into therapeutics by Brunton, who advised their use in angina pectoris to relieve^ sj^asm of the arteries. They are certainly the most powerfuT depres- sants oi the blood-pressure known, and may be used in all cases where this appears abnormally high. For rapid transient effects nitrite of amyl seems specially indicated, while nitroglycerin and nitrite of so- THE NITRITES. 471 dinm are more suited to produce a depression of some duration. Thus during the attack of angina pectoris, amyl nitrite is often found to give instant relief, but if nitrite of soda is administered every 4-6 hours, no attack may occur. The disadvantage of the metallic nitrites is the fre- quent eructation they produce, while nitroglycerin often causes severe headache, which, however, disappears in some cases after repeated use. Besides in angina pectoris, the nitrite series may be used in any con- dition in which it is supposed that the arterial tension may be lowered with benefit to the economy. Thus nitroglycerin has been advised in heart disease and has accordingly been placed by some among the heterogeneous group of " Cardiac tonics or stimulants." Its beneficial effects are not due to any direct action on the heart, but to its decreas- ing the resistance against which the systole is performed. In this way the contraction of the ventricle is rendered more complete, and the output of the heart may be increased. In weak hearts struggling against a high aortic resistance, this relief may be followed by marked benefit, and for this reason nitrite preparations (nitroglycerin) are often prescribed in chronic Bright' s disease. Digitalis causes a contraction of the peripheral arterioles along with its proper cardiac action, and the addition of nitrite may be advisable in some cases in order to neutralize this peripheral action. In those cases the nitrite of soda or nitrogly- cerin is of course preferable to amyl nitrite, whose action is too transient. (See Digitalis, page 455.) Amyl nitrite has been advised in accidents during chloroform anesthesia on the theory that it would benefit the circulation ; but, as a matter of fact, it would appear strongly contra- indicated in those cases in which it is true that the heart is extremely depressed, but in which the arterial tension is practically zero. Its use is especially irrational if, as has been suggested, the failure of the respira- tion is partly due to anaemia of the central nervous system. The cases iu which recovery has occurred after this measure may, in fact, be said to have recovered not owing to, but in spite of the use of amyl nitrite. In very advanced degeneration of the cardiac muscle fibre, the ad- mi nistrationofaniyT nitrite is distinctly contrainclicated, for the blood- pressure is low and any further reduction may lead to syncope from anemia of the brain, and to still greater weakness of the heart from the low pressure in the coronary arteries lessening its nutrition. Nitrite of amyl has been used largely in asthma and in cardiac dyspnoea. Its action is often beneficial and has been attributed to its depressing the bronchial muscles, which are supposed to be in a con- dition of spasmodic contraction in asthma. In the cardiac cases its *.MMMMMMMMB4MaMMaiNM*!* i-i .. i j.1 action in removing the dyspnoea may be due to its lowering the pres- sure in the systemic arteries and thus relieving the heart. In some cases of headache, nitrite of amyl is of marked benefit, while in others it aggravates the condition. This is perfectly intel- ligible, as some forms of headache may be due to constriction of the arterioles while others are accompanied by a congested condition of the vessels of the head. From spasm oFthe circulatory organs, the use of nitrite of amyl 472 ORGANIC DRUGS ACTING AFTER ABSORPTION. has been extended to other forms of spasmodic seizures, such as epi- lepsy. It seems to be of little or no value, as indeed might be ex- pected from its pharmacological action. In some cases it even seems to increase the tendency to convulsions. Sweet spirits of nitre has long enjoyed a popular reputation as a diaphoretic and diuretic. It seems to have little action either on the kidneys or the sweat glands, and might be discarded from the phar- macopoeia without loss. It is of more value as a carminative and flavor than for any other purpose. BIBLIOGRAPHY. Brunton. Arbeiten aus der pliysiolog. Anstalt, zu Leipzig, iv., p. 101, and Journ, of Anat. and Phys., v., p. 92. Wood. Amer. Journ. of Med. Sciences, Ixi., p. 422. Atkinson. Journ. of Anat. u. Phys., xxii., p. 225. Mayer u. Friedrich. Arch. f. exp. Path. u. Pharra., v., p. 55. Hay. Practitioner, xxx., pp. 179-321. Leech. British Medical Journal, 1893, Vols. i., p. 1305 and ii., p. 4. Cash and Dunstan. Phil. Trans, of the Royal Soc., clxxxiv., B., p. 505. Gamgee. Ibid., clviii., p. 589. Giacosa. Ztschr. f. physiolog. Chemie, iii., p. 54. Mitchell and Reichert. Amer. Journ. of the Medical Sciences, Ixxx., p. 158. Haldane, Makgill and Mavrogordato. Journal of Physiology, xxi., p. 160. Schadow. Arch. f. exp. Path. u. Pharm., vi., 194. Filehne. Arch. f. Anat. u. Phys., 1879, p. 385. Marshall. Jour, of Phys., xxii., p. 1. Bradbury. Brit. Med. Journ., 1895, ii., p. 1213. C. Rosenthal. Archiv f. [Anat, u.] Phys., 1888, p. 29. W. Rosenthal. Ibid., 1893. Supplement, p. 240. Laws. Journ. of Amer. Med. Ass., xxxi., p. 793. Winkler. Ztschr. f.'klin. Med., xxxv., p. 213 ; xxxvi., pp. 30, 138. XXXI. ERGOT. Ergot is a parasitic fungus (Claviceps purpurea) which grows on the rye (Secale cerealej and occasionally ou other kinds of grain, more rarely on other plants. It is of great importance in therapeutics and also in toxicology, as the use of bread and meal containing it has fre- quently given rise to widespread epidemics. In these the chief symp- toms consisted in gangrene of the limbs or in convulsive movements and contractures. The chemistry of ergot is still in an unsatisfactory condition, as its active principles seem to be peculiarly unstable, and are decomposed by compara- tively weak reagents. A large number of imperfectly isolated bodies have been described as occurring in it, but the first approach to a successful treat- ment of the subject was made by Kobert in 1884. He described three bodies as involved in the action of ergot, the first, Ergotinic Acid, a nitrogenous acid of glucosidal nature, the second, Cornutine, an alkaloid, and the third, Sphacelinic Acid, a resinous acid which contains no nitrogen. Various other bases have been observed in ergot besides cornutine, but most of them are entirely inert, and the others may owe their action to the presence of one or more of these three bodies, or may perhaps be identical with cornutine. It must be added that Kobert did not succeed in isolating completely any of these three poisons, but he was able to show that, while ergotinic acid be- haves in the same way as the members of the sapotoxin series, cornutine ERGOT. 473 stimulates the central nervous system strongly and produces convulsions, while sphacelinic acid induces gangrene in animals. Jacobj has recently stated that the action of sphacelinic acid is due to a very poisonous resinous body, Sphacelotoxin, which seems to be capable of entering into loose combinations with various other constituents of ergot. He succeeded in isolating two such compounds, one of which, Chrysotoxin proved to be a combination of sphacelotoxin with the weakly acid, inactive body, Ergochrysin, the other of which Secalintoxin, was a similar compound of sphacelotoxin and an alkaloid, Secaline. Sphacelotoxin he found to be a very unstable compound, which kept better when in the form of chrysotoxin. The action of ergot as known at present is therefore a complex which may be analyzed into three factors : 1. That due to one or more bodies somewhat resembling sapotoxin in action and contained in an impure form in the ergotinic acid of Kobert. 2. That due to one or more convulsive poisons contained in the cornutine of Kobert, and 3, that due to a gangrene-producing poison, which is contained in the spha- celinic acid of Kobert, and has been termed sphacelotoxin by Jacobj. While Cornutine is not a pure principle and its effects may be due to the interaction of several poisons, the train of symptoms is per- fectly distinct from those induced by the other constituents of ergot, and the name may be used to indicate the cause of these, without any definite understanding as to the nature of the body. In frogs it induces changes in the skeletal muscles similar to those described under veratrine, but, unlike the latter, does not affect the heart. In both frogs and mammals convulsions are observed and seem to be due to stimulation of the medulla oblongata and the basal ganglia, for they disappear in the frog when the medulla oblongata is destroyed, and are mainly clonic in nature. In the dog the symptoms consist of rest- lessness, salivation, vomiting, and purging. The pulse is slow and irregular, and after somewhat larger doses clonic convulsions set in with intervals of depression. The respiration ceases during one of these, while the heart continues to beat for some time. The alteration in the contraction of the muscles is due to direct action on the muscular fibre, similar to that of veratrine, while the other symptoms, like those from picrotoxin, are caused by stimulation of the medulla oblongata and the nervous centres in its neighborhood. The slow rhythm of the heart can be removed by section of the vagi, and isjFerefor.e,diie,to the inhibitory .centre. The vaso-constrictor centre is also stimulated, and a considerable increase in the arterial pressure is thus caused, although this may be concealed by the slowness of the heart. Neither heart nor vessels are affected directly. The nausea, salivation and vomiting seem to be the result of medullary action also. Kobert observed that both stomach and bowel contracted powerfully under cornutine, and that wave-like movements occurred at the same time in the uterus, whether pregnant or not. These movements were not continuous, but resembled peristaltic contractions and did not tend to empty the uterus. They were not produced in the excised organ when it was perfused with blood containing cornutine, and he there- 474 ORGANIC DRUGS ACTING AFTER ABSORPTION. fore supposed that they were the result of some action on the central nervous system. After large doses of cornutine the stimulation of the central nervous system passes into paralysis and the respiration ceases. Sphacelotoxin diifers from all other known poisons in producing gangrene of various organs, more especially in fowls and pigs. In the frog the symptoms consist of depression and paralysis of the central nervous system. In most mammals (dogs, cats, rabbits, and guinea-pigs) the chief symptoms arise from irritation of the ali- mentary canal salivation, vomiting and some purging which is induced whether the drug be administered by the mouth or subcuta- neously. Later some signs of excitement may be observed, followed by depression and weakness, the excitement apparently being due to cerebral action. Robert found numerous extravasations of blood in the stomach, intestine, and other organs, especially when the drug was given for some time and chronic poisoning induced. No gangrene could be elicited in these animals. In fowls a much more characteristic train of symptoms is found to follow the administration of sphacelotoxin. A cock soon appears drowsy and somewhat dyspnoeic, and the comb loses its bright scarlet color and becomes blue and cyanotic, especially at the tips. Purging and sometimes vomiting follow, and the animal has often great diffi- culty in preserving its balance, swaying to and fro very much as does a patient suffering from locomotor ataxia. After small doses the symptoms may pass off, but when larger quantities have been injected, and especially if chronic poisoning is induced, the comb becomes dry and hard and eventually falls off without any haemorrhage. The wattles, tip of the tongue, wings and spurs may undergo the same process. It refuses food, loses flesh and becomes weak and somnolent, but may recover if the treatment be stopped ; otherwise it dies of inanition and general weakness. The vessels of the comb are found to be filled with a transparent " hyaline " mass with a narrow streak of red corpuscles here and there, and it is evident that a typical dry gangrene has been induced. Marked irritation of the mucous mem- brane of the crop, stomach and bowel is present, with numerous ex- travasations, frequently with circumscribed areas of necrosis. (Edema and ecchymoses are often met with in the subcutaneous tissue and also in the internal organs, and a curious substance resembling amyloid was seen in the liver by Griinfeld. No alteration of the central ner- vous system has been detected after careful examination. In pigs, the ears become dark-colored and cyanotic and the tips undergo dry gangrene and fall off. Gangrene is also observed in the extremities and in different parts of the skin of the trunk, and hemorrhages into internal organs occur, especially in the bowel. The gangrene appears to be due to a prolonged contraction of the arterioles shutting off the blood supply of the parts and leading to a hyaline formation in the lumen and walls of the arterioles, which effectually obstructs the circulation after the muscular coats have relaxed. The constriction of the arterioles has been shown to occur in ERGOT. 475 animals in which no gangrene follows, but is probably not so extreme in these. This constriction of the arterioles of course induces an increase in the blood-pressure, which was found by Robert to be of considerable extent, while Jacobj found it less marked. Curiously enough, the blood-pressure in the fowl has not been examined under sphacelotoxin, although it might be expected to be more augmented in these than in many other animals. Robert supposed that the arterioles were constricted by the increased activity of the vaso-motor centre, but Jacobj has shown that there is also some peripheral action, for the blood-pressure rises after division of the spinal cord, and the flow of blood through an excised organ is considerably retarded when sphacelotoxin is added to it. He there- fore considers that the muscular wall of the vessels is acted on directly, as well as through the central nervous system. Jacobj found that sphacelotoxin often induced abortion in pregnant animals, and concludes that it provokes uterine contractions, which are not tetanic in nature, but which rather resemble the normal peri- staltic contractions of the uterus during labor. These wave-like con- tractions move the foetus towards the os uteri, and eventually cause its expulsion. He found that abortion could be induced without serious injury to either parent or young. The contractions of the uterus may be due to some action on the spinal cord, as has been generally believed, but it must not be forgotten that the uterus is capable of automatic movement and that the young can be expelled from it after destruc- tion of the spinal cord, so that it seems not unlikely that ergot acts rather on the uterine fibres directly than through the nervous centres. This uterine action is elicited in animals in which ergot does not induce gangrene, such as the rabbit and cat. Palm has recently confirmed Jacobj's results, and extended them by showing that sphacelotoxin induces contractions of the uterus in patients during labor. After small doses the pains resemble those occurring naturally, but large quantities cause a tetanic contraction of the uterus, which may seriously injure the child. The Ergotinic Acid of Robert seems to have little or no effect when given by the mouth, but induces depression and paralysis of the spinal cord when injected subcutaneously or intravenously in frogs and mammals. The higher divisions of the nervous system seem less readily affected, although the brain is also depressed, and unconsciousness and collapse may follow. The blood-pressure is much reduced from depression of the vaso-motor centre, while the heart seems comparatively little affected. Death occurs from paralysis of the respiratory centre. In addition to these three bodies there are probably other active principles contained in ergot, for some preparations of the drug cause very distinct slowness and weakness of the pulse, which does not seem to be induced by any of the three constituents described above. None of the principles have been extensively used in medicine except in impure forms. Ergot has rarely given rise to Acute Poisoning in Man, but in several cases in which it was taken in order to induce abortion, the symptoms consisted in collapse, with a weak, rapid pulse, tingling, itching and 476 ORGANIC DRUGS ACTING AFTER ABSORPTION. coldness of the skin, unquenchable thirst, vomiting and diarrhoea, confusion or unconsciousness, haemorrhages from the uterus, abortion, and some icterus. Ecchymoses were found in the subcutaneous tissue and in many internal organs. Somewhat similar symptoms have been produced in animals. Chronic Poisoning was formerly not uncommon, and in fact frequently gave rise to widespread epidemics, from the use of bread containing ergot after poor harvests and especially in wet seasons. Of late years these epidemics have become rare except in Russia, but some of the " plagues " of mediaeval Europe may have been due to ergot poisoning. The symptoms of ergotism are sharply divided into two groups, those of gangrene and those of nervous disorders. In some epidemics both the gangrenous and the convulsive forms are present, but, as a general rule, one is much more prevalent than the other, at one time gangrene being almost invariably present, while in another epidemic, the convulsive type is the more common. The gangrene is generally developed in the limbs, especially in the fingers and toes ; sometimes the whole arm or leg becomes cold and anaesthetic, dark in color, and then dry, hard and shrunken, and falls off with little or no pain and no hemorrhage. Symptoms of such severity are rare, however, and in milder cases only the skin necroses. Gangrene of internal organs also occurs, resulting in cataract in the lens of the eye, or ulcers in the bowel and stomach, and sometimes affecting a whole organ such as a lung or the uterus. Abortion is seldom mentioned in the accounts of chronic ergot poisoning, and pregnancy seems in many cases to have run its ordinary course. Gangrenous ergotism is evidently due to sphacelotoxin causing prolonged contraction of the vessels, followed by hyaline thrombosis. The blood vessels in man therefore seem to be acted on in the same way as those of the fowl and pig, while those of the other mammals escape. In spasmodic ergotism the first symptoms are depression, weakness and drowsiness, often with headache and giddiness, painful cramps in the limbs, and itching and formication of the skin. In severe cases paroxysmal convulsions set in, generally clonic, and often epileptiform, but leaving as sequelae contractures in the limbs, or less often in the trunk muscles. Some intellectual weakness often follows recovery from ergot poisoning, this not infrequently amounting to complete dementia, but the disease was immediately fatal in a large proportion of cases in earlier times. Cornutine was supposed by Kobert to be the cause of the convulsive form of ergot poisoning, and his explanation has been generally accepted, although it is not without difficulties, for chronic poisoning with cornutine does not produce any symptoms whatever in animals, unless doses sufficient to cause acute poisoning are given. On the other hand, fowls poisoned with sphacelotoxin suffer from ataxia and other nervous symptoms, so that it is probable that other factors besides cornutine are involved in the production of these symptoms in epidemic poisoning and the entire action may perhaps be due to sphacelotoxin. ERGOT. 477 The accounts of different observers of the action of ergot on the individual organs present great discrepancies. This is explained by the difference be- tween the preparations used and by the extreme instability of the more active principles. The effects on the circulation are especially liable to vary, for in many cases the heart is rendered slow and weak, sometimes apparently from cornutine acting on the vagus centre, at other times from some unknown body affecting the muscle directly ; in others acceleration of the heart has been observed. Very often the preparations known as ergo tin are stated to cause a very marked fall in blood-pressure, while others which probably contain larger amounts of sphacelotoxin and cornutine contract the arterioles and increase the blood-pressure. Further dispute has arisen as to whether this effect is central or peripheral. It is obviously unprofitable to discuss these questions, however, as scarcely any two of the investigators have used the same preparation, and there is no means of judging of what constituents their drugs were composed. The effects of ergot and its preparations on the Uterus are no less a matter of dispute. Many gynaecologists consider that it does not excite movements in the uterus, but that when labor has commenced, it pro- longs the contractions and may, in fact, cause a continuous contrac- tion (tetanus) of the muscular fibres, which delays the expulsion of the contents and imperils the life of both mother and child. On the other hand, some believe that ergot induces uterine contractions and strengthens those present in labor, without necessarily hindering the periodic relaxation of the muscle, and Jacobj's and Palm's results with sphacelotoxin would confirm the latter view. These discrepancies are undoubtedly to be explained by the fact that preparations of ergot are very often employed which are entirely inert, while in other cases effects have been credited to ergot which have appeared before it was possible that the drug was absorbed. The action of ergot on the uterus is not suffi- ciently certain to permit of definite statements, but it seems unquestion- able that in animals it produces abortion, and must therefore induce move- ments similar to those occurring in normal labor. It is probable that in the human uterus the same effect is induced, while the so-called " tetanus uteri " may perhaps be explained by the use of large doses or very active preparations. It may very well happen that a substance which in small quantities only increases the irritability of the muscle or strengthens the normal contractions, may induce very prolonged contractions when applied in larger quantities (compare the action of digitalis on the frog's heart). Some experiments have been performed to find whether the contrac- tions of the uterus under ergot are due to action on the uterus itself or on the nervous centres. But the results are again contradictory and need not be detailed. Robert at first supposed that sphacelotoxin was the more important body in the action of ergot on the uterus, and this view has been held by most authors since then, and has been supported in particular by Jacobj. Of late years, however, Robert has come to regard cornutine as the chief factor in this result, although there seems no satisfactory work, either experimental or clinical, in support of his more recent view. The vomiting and diarrhoea which are sometimes observed after ergot may be of central origin, but are generally supposed to be due to 478 ORGANIC DRUGS ACTING AFTER ABSORPTION. direct action on the muscular coats of the stomach and intestines sim- ilar to that described by some authors as occurring in the uterus. PREPARATIONS. U. S. P. Ergota, ergot of rye, the sclerotium of Claviceps purpurea re- placing the grain of rye. When more than one year old it is unfit for use. Extractum Ergots, 0.2-1 G. (3-15 grs.). FLUIDEXTRACTUM ERGOT^E, 4-8 c.c. (1-2 fl. drs.). Vinum Ergotse, 10-20 c.c. (5-10 fl. drs.). B. P. Ergota, the sclerotium of Claviceps purpurea, originating in the ovary of Secale cereale. 20-60 grs. Extractum Ergotse (Ergotiu), 2-8 grs. EXTRACTUM ERGOTS LIQUIDUM, 10-30 mins. Tinctura Ergotse Ammoniata, \ 1 fl. dr. Infusum Ergotse, 1-2 fl. oz. INJECTIO ERGOT.E HYPODERMIC A, 3-10 mins. (subcutaneously). The in- jection ought to be recently prepared. It is about 33 per cent. The fluid or liquid extracts and the hypodermic injection are the best of the preparations. The vinum is very often quite inert, and the extract being prepared from the fluid extract by heat is liable to contain less of the un- stable active constituents than the latter. A very large number of prepa- rations, such as ergotin, ergotinic acid, sclerotinic acid, cornutine, etc. , are simply more or less purified extracts and have no advantage over the phar- macopceial preparations ; in fact the chemical manipulations through which they are obtained are often such as are likely to remove, or render inert, the active bodies of the crude drug. The dose of the preparations of ergot is exceedingly variable, as a quantity sufficient to induce very marked effect in autumn, may be found entirely inert in the following spring. Griinfeld, in fact, states that in March and April twelve times as much is required as in July and August, and that in May and June the drug is entirely without effect in any dose, but this is probably an exaggeration, unless where the ergot has been carelessly stored. Accord- ing to Jacobj , the pure chrysotoxin may be kept for years without deterior- ating. Sterilized fluid extract is said to keep better than the ordinary preparations, but the whole subject requires further research. Therapeutic Uses. Ergot is used very largely in obstetrics to pro- mote the contraction of the uterus, but considerable divergence is met with in the views of different authorities as to the special indications for its exhibition. Thus, those who believe that ergot increases the irritability of the uterus and produces rhythmical contraction without tetanus, advise that it be given whenever the pains seem insufficient, and more especially when this occurs in the later stages of labor. Others are possessed with perhaps an exaggerated apprehension of the prolonged uterine contractions, which they consider delay labor and tend to cause asphyxia in the child, and therefore advise that ergot be used only to preserve the uterus in a contracted condition after the child and placenta have been expelled. In every case the attendant should of course satisfy himself before giving ergot of the absence of all actual impediments to the passage of the child, such as contracted pelvis, abnormal presentation, or great rigidity of the soft parts, and when it is administered before the head emerges, the dose ought to be small, as otherwise the tonic contraction may be induced. When the ERGOT. 479 head is about to emerge, on the other hand, a large dose may be given to promote the permanent contraction of the uterus and thus to pre- vent post-partum haemorrhage. When the latter has once set in, er- got is of less immediate service, as it is slowly absorbed, and no ef- fects follow for some twenty minutes or more. Whenever there is any reason to fear that weakness of the uterine contraction and haemor- rhage may set in after the expulsion of the child, ergot ought to be given when the head emerges, and many gynecologists recommend this as a routine treatment. Ergot hinders post-partum hemorrhage, chiefly by promoting the contraction of the uterus. In other forms of hemorrhage from the stomach, intestines, kidneys, lung or uterus in which the bleeding point cannot be reached, it is often advocated in the belief that it con- tracts the walls of the vessels and thus arrests the flow of blood. These hemorrhages so often cease spontaneously that it is difficult to estimate the value of any remedy, but it may be questioned whether ergot merits its reputation in these cases. Its action in healthy ani- mals certainly indicates that the contraction of the vessels is confined to certain organs, otherwise there would be a more distinct increase in the blood-pressure. And there is no reason to suppose that a more intense action is exerted on a ruptured vessel than on the uninjured ones of other organs ; but unless this is the case the use of ergot may be rather harmful than remedial, for any increase in the general blood- pressure, such as would follow the contraction of the vessels through- out the body, must increase the escape of blood from the injured ves- sel. In these cases, as in labor, the fluid extract is often given by the mouth, but this extract or the special preparation of the B. P. is sometimes injected .with the hypodermic needle. It is irritant, and ought therefore to be injected deeply into the muscle, rather than into the subcutaneous tissues. The effect of ergot in inducing contraction of the uterus has been used in the treatment of subinvolution and of myomata of that organ ; the involution of the uterus certainly seems to be favored by it, but the results in tumor are more open to question. In any case the prolonged treatment of this, or of any other condition with ergot is to be deprecated, for if the drug is active at all, it may induce gan- grene or spasmodic ergotism. The same criticism might be applied to the ergot treatment of a number of other diseases, such as aneurism, diabetes, or pneumonia ; and in addition, it does not seem to have any greater effect in these than many other less dangerous remedies, which have been equally vaunted as specifics, and have been found equally valueless. BIBLIOGRAPHY. Robert Arch. f. exp. Path. u. Pharra., xviii., p. 316. Griinfdd. Arb. a. d. pharmakol. Institute zu Dorpat, vii., p. 108; xii., p. 295. Jacob}. Arch. f. exp. Path. u. Pharm., xxxix., p. 85. Houghton. Therap. Gazette, 1898, p. 433. Walker. Arch. f. Psychiatric, xxv., p. 383. Jahrmdrker. Ibid., xxxv., p. 109. 480 ORGANIC DRUGS ACTING AFTER ABSORPTION. Palm. Arch. f. Gynaekologie, Ixvii. Santesson: Skand. Arch. f. Physiol., xiii., p. 107. The earlier literature is to be found in Griinfeld's paper, but the student is recom- mended to read the above papers before proceeding to the earlier work. TIstilagO Maydis (U. S. P.), or corn smut, a fungus growing on maize, is entirely different from ergot, and, according to Robert, is quite inert. It has been used as a substitute for ergot, on the supposition that it would resemble it in action as well as in origin, but has proved quite ineffective. Cotton-root Bark (Gossypii Cortex (U. S. P.)) has been used by the Southern negroes to produce abortion, and is said by some gynecologists to resemble ergot in action on the uterus. It has little or no effect on animals, except in enor- mous doses, and is generally stated by those who have tested it to be entirely devoid of action in man. PART III. COMBINATIONS OF THE ALKALIES, ALKALINE EARTHS, ACIDS AND ALLIED BODIES. SALT-ACTION. THE action of most of the substances discussed in the foregoing pages may be best explained by supposing that they cause some change in the living matter of one or more organs through a specific chemical affinity for it. Thus strychnine may be supposed to act on the spinal cord by forming a chemical compound with the protoplasm of the nerve cells, while prussic acid changes protoplasm generally, through a similar affinity for it. Some bodies, on the other hand, seem to have little specific affinity for living matter, but affect it largely as they do dead colloid sub- stances, through changing the physical properties of the fluids contained in it or surrounding it. This action is seen best in the effects of some of the salts of the alkalies, and is therefore known as " salt-action," although it is not confined to these, but is shared by any soluble, diffusible body which can circulate in the tissues in sufficient quantity. The salts of strychnine or of prussic acid are undoubtedly capable of inducing physical changes similar to those observed after chloride of sodium, but they play no part in the symptoms induced by these poisons, because animals die from the specific action long before the quantity necessary to induce the " salt-action " can be absorbed. In the case of less poisonous organic substances, such as sugar and urea, however, many of the features of salt-action may be observed. Much light has been thrown on the nature of salt-action by the re- cent advances in physical chemistry, which have shown that many of the changes in the animal body are analogous to those observed in the chemical laboratory. When an aqueous solution of sugar or salt is carefully poured on distilled water, so that two layers are formed, a process of Diffusion commences, the dissolved molecules passing through- out the fluid until the whole becomes homogeneous, each cubic centi- metre containing an equal number of molecules of sugar or salt. If instead of distilled water, a solution of another salt be used, the same process results, the two bodies diffusing throughout both fluids until these become homogeneous ; and if the fluids be separated by a mem- brane which offers no obstacle to the penetration of the water and salts, a similar interchange occurs. When a membrane is used which does not allow the salt to pass through it, a different result is observed ; 31 481 482 INORGANIC SALTS, ACIDS AND BASES. if it separates salt solution from pure water, the latter passes through until it is exhausted, or until some factor such as hydrostatic pressure puts a limit to further movement. This is readily intelligible, for the pure water can pass without hindrance towards the salt, but having rendered the solution more dilute, it cannot diffuse in the opposite direction, because this would be equivalent to forming a more concen- trated solution of the salt, and this requires the expenditure of energy, such as heat, while in the case in point there is no energy available for this purpose. A similar result is obtained if the membrane separate solutions of a non-permeating and of a permeating salt, the latter passing through with the fluid in which it is dissolved until some ex- traneous factor counterbalances the diffusion. The resistance offered by a non-permeating salt to the passage through the membrane of the fluid in which it is dissolved is known as the Osmotic Pressure of the solution and varies with the number of molecules and ions (see page 484). When both the salts in solution on the opposite sides of the membrane are unable to penetrate through it, the move- ment of the fluid is determined by the relative osmotic pressure on the two sides, water tending to pass from the solution with the lower osmotic pressure (the hypotonic solution) to that with the higher (hyper- tonic) until an equilibrium is established by the osmotic pressure be- coming equal on the two sides, when the solutions are said to be isotonic. As a general rule, however, membranes are partially permeable to both salts, and the movement of the fluid is determined by the relative osmotic pressure of the fluids divided by the rate at which the salts pass through the membrane. If sufficient time is allowed to elapse, the two solutions will become identical in composition, but during a short period, the details of the process are difficult to follow, and the complexity is infinitely greater when instead of a single salt on each side of the membrane there are several salts each differing in its per- meability and concentration. The direction of the flow is then deter- mined by the sum of the osmotic pressure on each side divided by the penetrating power of each individual substance. In the animal body such membranes as are used in physical experi- ments are not met with, but the cells consist of colloid substances con- taining fluid and diffusible bodies, and are surrounded by liquids which are practically salt solutions isotonic with the contents of the cells ; any change in the contents of the cell or in the lymph surrounding it must of necessity give rise to a certain movement of the fluids in the same way as if each cell were surrounded by a membrane. All the ceils of the body are permeable by water, and a dilution of the fluids surrounding them is therefore followed by an increase in their fluid contents and swelling. On the other hand, some salts seem to diffuse into cells practically without resistance, while others fail altogether to do so, or penetrate only very slowly. The subject has been investi- gated with most care in the red blood cells, which are found to be pene- trated by ammonium chloride and some other salts, while they are impermeable by sodium chloride and the other salts of the fixed SALT-ACTION. 483 alkalies. Accordingly, when the red blood cells are surrounded by a solution of ammonium chloride, whatever its concentration, their fluid contents are increased ; they swell up and eventually lose their haemo- globin, exactly as if they had been placed in pure water. When they are placed in an isotonic solution of chloride of sodium, 1 they remain unchanged in size, while in a hypertonic solution their fluid dif- fuses out, and they shrink ; a hypotonic solution acts like pure water, the osmotic pressure of the salts in the corpuscles overcoming the smaller osmotic pressure of the surrounding fluid. The behavior of a cell towards salts therefore varies with each individual salt. Solu- tions of those by which it is perfectly permeable have the same ef- fects as pure water ; but the less diffusible the salt, the more tendency it has to prevent the entrance of the water in which it is dissolved, and if in sufficient concentration, to withdraw fluid from the cell. A per- fectly diffusible substance can never prevent the entrance of fluid, however concentrated be its solution. All the cells of the body do not resemble each other in their per- meability, nor in the salts which diffuse into them. For example, the intestinal epithelium takes up some of the salts of the alkalies, while the red blood cells do not. An even more obscure relation between the salts and colloids has been discovered by Hofmeister, who found that gelatin plates thrown into weak salt solutions absorb more fluid than when they are put in distilled water, and who inferred from this that colloid substances have a special affinity for salts quite apart from their permeability by water, and that they are not merely passively permeated by salt solu- tions, but have an active attraction for some of the salts contained in them. This affinity, which may depend on the same factor as the permeability of the cell, varies for different salts. The role played by the physical forces in the salt-action is thus determined not only by the physical properties of the fluids, but also by the "affinity " of the cell contents for certain of the constituents of these fluids. In con- clusion it may be stated that these physical forces are not sufficient to explain the whole processes of absorption and excretion, as has sometimes been stated ; the physical forces merely influence the processes of nutrition, which depend on forces hitherto unexplained and possibly exercised only by the living proto- plasm. The penetrating power of salts seems to be connected with the property which many of the a possess of precipitating certain colloid substances from their solutions in water, for those salts which permeate gelatin plates are found to precipitate colloids less than others. Thus the sulphates of the alka- lies, which permeate gelatin plates with difficulty, throw globulins out of Solution much more readily than the chlorides. Here again, however, different colloids vary in their affinities, some reacting to one sulphate and not to another. This reaction is not confined to the proteids but extends to many carbohydrate colloid substances. In the dilute solutions found in the tissues, the salts do not exist as 1 An isotonic solution is here used to indicate a solution in which the osmotic pressure is equal to that of the blood serum, and (presumably) to that of the contents of the red blood cells. 484 INORGANIC SALTS, ACIDS AND EASES. such, but are largely dissociated into two or more Ions charged with positive and negative electricity. Thus if a small quantity of potassic chloride be dissolved in water, it is dissociated into a positive K ion (Ration) and a negative Cl ion (Anion). 1 Similarly sodium sulphate dissolved in water exists as two Na ions and a negative SO 4 ion. One effect of this is that the osmotic pressure of such a dilute solution diverges considerably from what might be expected if it were calcu- lated from the number of molecules present, because each of the ions exerts the same osmotic pressure as a whole molecule. But a more im- portant fact is that the ions of a salt, and not the whole molecule, form chemical combinations, and thus exert their pharmacological action. Thus what is known as the action of many poisons is really the action not of the molecule as a whole, but of one of the ions. For example, cyanide of potassium is said to possess a very poisonous action, but this is due not to the molecule KCN as such, but to the CN ion, which forms from it in solution. When ferrocyanide of potassium is dissolved, on the other hand, no CN ion is formed, the salt dissociat- ing into the K and Fe (CN)^ ions, and ferrocyanide of potash is there- fore entirely devoid of the cyanide action. In the same way the corrosive effects of potassium or sodium hydrate are not due to the potassium or sodium, but to the hydroxyl ions (HO), for the same K or Na ions are obtained when KC1 or NaCl is dissolved, but neither of these is corrosive. Thus when a dissociable body is administered, not one, but two, separate agents are put in action in the tissues, and in describing the effects of one of these dissociable bodies, the effects of each ion have to be taken into consideration. In the organic materia medica, many such substances occur, but in the great majority of them the action of one ion is so much more powerful than that of the other that the less important one may be neglected. Thus, mor- phine sulphate in the body exists as a morphine and a sulphate ion, but the action of morphine is so much the more powerful that the sul- phate ion may be left out of account. This is shown by the fact that morphine hydrochlorate, which is dissociated into morphine and chlo- ride ions, has practically the same action as morphine sulphate. In the same way the positive ion (Na, K, etc.) of the cyanides may be neglected, because the negative CN ion is so poisonous that the posi- tive ion can never be present in the tissues in sufficient quantity to elicit any action. When, however, less poisonous substances are involved, the case is quite different. Thus, although the hydrobromate and the sulphate of morphine may be described as possessing the same action, because the morphine ion alone is taken into account, the sulphate and brom- ide of potassium induce quite different symptoms, 2 because here larger 1 These ions are not to be confused with atoms of potassium and chlorine for they possess none of the cheaiical properties of these elements ; the physical difference con- sists in each ion being charged with a burden of electricity, positive or negative. 2 Even at the present day it is sometimes a matter of discussion whether the bases or the acids are the determining factors in the action of the salts of the alkalies. The question depends entirely upon which salts are compared. If chloride of sodium and SALT-ACTION. 485 quantities can be administered, and the SO 4 and Br ions are present in sufficient quantities to elicit their specific action, which is quite as important as that of the K ion. In this connection it is to be noted that many bodies are not disso- ciated. For example, potash, KHO, and alcohol, C 2 H_HO, both con- tain HO, but in the former the hydroxyl is dissociated in water, while the latter remains undissociated. Thus, when KHO comes in contact with a mucous membrane, the molecule does not act as such, but the effects are due to the HO ion, and to a less extent, to the K ion. On the other hand, alcohol acts as a molecule, and the caustic effects of the HO ion are not observed under it. A similar contrast is offered by the effects of the dissociable KBr and bromated camphor, which is not dissociable but acts as an entire molecule. It is therefore vain to expect the bromide action from this compound, for the bromides act from the presence of the bromide ion, which is not formed from mouobromated camphor. This renders the classification of the inorganic salts a matter of some difficulty, for it is necessary to consider the action of each ion alone, and then to find how far its effects are modified by the presence of the other ion with which it is associated in the molecule. It is obviously illogical to consider under a " potassium series" all the salts of potash, for in many of these the K ion is of no importance, while in others it is the chief factor. The effects of an ion cannot be determined except by administering it along with another in the form of a salt, but certain ions are so inac- tive in the tissues that if any effect is noted after a compound of which they form part, the action can be ascribed with certainty to the other ion, unless the change arises from alteration of the physical prop- erties of the fluids. For example, the sodium ion (Na) and the chloride ion (Cl) are both practically inert, except in so far as they change the osmotic pressure. Thus, if a sodium salt or a chloride be found to cause some change which is not due to the physical alteration, the ac- tion is attributed to the other ion of the molecule. Before entering on the study of the action on the ions, however, it is obviously neces- sary to learn the symptoms caused by alteration of the physical prop- erties of the fluids, and this can best be done by examining the effects of bodies which act only in this way, namely, chloride of sodium and water. BIBLIOGRAPHY. Naegeli. Pflanzenphysiologische Untersuchungen, 1855. De Vries. Pringsheim's Jahrb. f. wissenschaft. Botanik, xiv., p. 427. Eykmann. Pfliiger's Arch., Ixviii., p. 58. Hedin. Ibid., Ixx., p. 525. Koeppe. Ibid., Ixvii., p. 189. Gryns. Ibid., Ixiii., p. 86. chloride of potash be compared, the determining factor is the base, but if a chloride and a cyanide be in question, the base with which they are combined is practically of no importance. 486 INORGANIC SALTS, ACIDS AND BASES. Hqfmeister. Arch. f. exp. Path. u. Pharm., xxiv., p. 247 ; xxv., p. 1 ; xxvii., p. 395 ; xxviii., p. 210. Hamburger. Osmotische Druck und lonenlehre, 1904. PaulL Beitrage z. chem. Phys. u. Path., ii., iii., v. Pohl. Zts. f. physiol. Chera., xiv., p. 151. For the adaptation of the theory of ions to pharmacology, consult : Scheurlen. Arch. f. exp. Path. u. Pharm., xxxvii., p. 74. Scheurlenu. Spiro. -Munch, med. Woch., 1897, p. 81. Loeb. Pfliiger's Arch., Ixix., p. 1. Schmiedebery. Grundriss der Arzneimittellehre, 3d ed., pp. 241-243. Kronig u. Paul. Zts. f. Hyg., xxv., p. 1. I. SODIUM CHLORIDE AND WATER. The most typical example of salt-action is presented by chloride of sodium, for this salt is always present in large quantities in the body, and has practically no specific action ; the sodium and chloride ions are ordinary and necessary constituents of the fluids of the body. The action of this salt is therefore limited to the alteration in the physical properties of the fluids, which its presence in excess or in limited amount induces. In the same way the action of water is due only to its diluting the body fluids and lessening their osmotic pressure, and it may therefore be described along with that of salt. Most of the tissues hitherto examined in regard to this point have proved permeable by both the Na and the Cl ions, but in every case there is a certain amount of resistance oifered so that the presence of salt in the fluid round a cell always prevents its free diffusion into the interior ; i. e., sodium chloride solution exerts osmotic pressure on the cell. The molecular weight of common salt being small, the osmotic changes induced by it are greater than those induced by an equal weight of most other salts, because a larger number of molecules ex- ist in each gramme. It also dissociates into its two ions more readily than many others, and this lends it still greater osmotic power. A common example of the osmotic action of salt is seen in its use to preserve meats from putrefaction, which it accomplishes by with- drawing the fluids of the meat, and thus rendering it dry and hard and unsuitable for the growth of microbes. In the same way the Red Blood Corpuscles shrink in size when they are placed in a solution of salt which is stronger than the blood-plasma (hypertouic), because the water is withdrawn from them. In dilute (hypotonic) solution, on the other hand, or in water, they swell up be- cause they absorb water, while in solutions of the same osmotic pres- sure as the plasma (iso tonic) they remain unaltered in size. When water is absorbed into the corpuscles some obscure change takes place in them, and the hemoglobin diffuses into the surrounding liquid. Muscle is affected in a similar way, strong salt solutions withdrawing fluid from it, while weaker ones are absorbed, and both tend to destroy its vitality in a longer or shorter time. In isotonic salt solution, on the other hand, muscle preserves its irritability for many hours. Strong salt solutions irritate exposed Nerves from the withdrawal of their fluid contents, and on the other hand, distilled water is equally fatal to them. SODIUM CHLORIDE AND WATER. 487 These changes are undoubtedly due to the imperfect permeability of the cells by the sodium and chloride ions, and as regards the red blood cor- puscles, it is definitely known that salt penetrates them with the greatest difficulty,if at all, and the changes induced in them by solutions of different concentration and by water are due to the alteration of their fluid contents only. If this were true for all cells, the isotonic solution would preserve them in a normal condition until they slowly perished for want of oxygen and from exhaustion of their reserve of food. But this is found not to be the case, for muscle suspended in isotonic solution often develops a more or less rhythmical series of contractions, while the frog's heart ceases to beat after a time when it is perfused with isotonic salt solution, although it has not exhausted its energy entirely. Similarly some ova and fish living in sea water die if they are put in a solution of sodium chloride isotonic with sea water while they live much longer in distilled water. It is obvious that in these instances no changs in the distribution of the fluids can occur, for the osmotic pressure of the fluid is unchanged. In other words the death of these animals in pure salt solution is due not to the physical action of the salt (salt action), but to . the sodium ion exercising a deleterious effect on them. This deleterious action may be neutralized by the addition of traces of salts of calcium or of some other bivalent elements, while the monovalent kations have less antagonistic effects (Loeb). In the natural environment of living cells both sodium and calcium are present, so that the toxic effect of sodium (see Calcium) can scarcely be observed except when small masses of tissue are thoroughly washed with salt solution ; as far as the higher animals are concerned, then, salt may be regarded as indifferent in itself and as acting only through changing the distribution of the fluids. And as isotonic solutions have no osmotic action, they are entirely inert. Water or very dilate salt solutions penetrate into the superficial cells of the Skin, which therefore become swollen and softened. Concen- trated solutions on the other hand rather tend to draw fluid from the surface cells, and this along with the passage of salt into them, causes some mild irritation. Neither salt nor water is absorbed into the cir- culation through the skin in mammals. A much greater absorption into the superficial tissues occurs on less protected parts, such as the cornea, which becomes white and clouded when strong salt solutions are applied to it. Similarly, either pure water or strong salt solution causes considerable pain and smarting in the nasal passages, or in wounds, from the disturbance of the normal relation of salt and fluid in the surface cells. Isotonic solutions on the other hand cause no pain. In the Mouth salt has a characteristic taste, and strong solutions act as astringents here and in the throat. In the Stomach its action is very much like that on other mucous membranes, hypotonic solutions causing swelling, while hypertonic solutions cause a withdrawal of fluid and a shrinking of the cells. This withdrawal of fluid and imbibition of salt may set up such irritation as to induce vomiting. The digestion in the stomach does not always seem to be improved by salt in the food, for even small quantities have been found to lessen the acidity of the gastric juice, and the amount of albuminous food ab- sorbed from the alimentary canal in animals is but little altered when salt is added to the food. It is very possible, however, that a small quantity of salt in the food renders it more palatable in many instances, 488 INORGANIC SALTS, ACIDS AND BASES. and thus increases the reflex flow of the gastric juice. (Compare Bitters, page 56.) Dapper finds that the hydrochloric acid of the stomach is increased in some persons, and diminished in others by mineral waters containing common salt as their chief ingredient. This is only to be explained by supposing that these waters have no effect on the secre- tion directly, but alter it by changing the nutrition of the gastric mucous membrane. Salt solutions are Absorbed both in the stomach and bowel, but con- siderable difference of opinion exists as to the means by which this is accomplished. An attempt has been made to explain absorption by the action of the known physical processes, such as diffusion, osmosis and filtration, but these seem quite inadequate without the assumption that there is a constant tendency for fluids and for some salts to pass inwards from the lumen of the bowel and stomach. This tendency may be opposed or strengthened by the osmotic pressure. Thus hypo- tonic solutions and water are absorbed rapidly, because here not only is the natural flow inwards, but the osmotic current is in the same direction, the fluid being of lower osmotic pressure than the blood serum ; but even pure water appears not to be absorbed from the stomach until it has acquired a certain content of salts which diffuse into it from the blood. In solutions of equal osmotic pressure with the blood serum the absorption is slower, because here the natural flow alone is active, while hypertonic solutions are still more slowly absorbed or may even be increased at first, because the osmotic pressure acts in the opposite direction from the natural flow. Accordingly, while hypo- tonic and isotonic solutions disappear rapidly, the absorption of the stronger solutions may be preceded by a period in which the fluid of the bowel actually increases, water diffusing into it from the blood. At the same time the salt is being absorbed, and the solution eventually becomes isotonic, and is absorbed. The absorption from the bowel is very similar to that described by Hofmeister in gelatine plates, and it is possible that the unexplained tendency for fluids to pass inwards may be due to some " affinity " between the salts and the colloids of the bowel wall. The Blood and Lymph are in turn affected by these processes. When hypotonic solutions pass into the blood from the bowel, the proportion of solids and liquid is of course changed, and fewer corpuscles and less solid matter are found in the cubic millimetre than normally (hydrse- mia). On the other hand, when strong salt solutions in the bowel cause the effusion of fluid, the blood becomes more concentrated than in ordinary conditions. After the reabsorption of the fluid, the normal balance of plasma and corpuscles must be restored, and to effect this currents are set up between the blood and the fluid of the surrounding lymph. These currents have been investigated by the injection of salt solutions directly into the blood, and not by their absorption from the bowel, but the processes probably resemble each other in their chief features. When the blood is rendered hypertonic by the injection of strong salt solution, the lymph at once begins to pour into the blood SODIUM CHLORIDE AND WATER. 489 vessels by osmotic attraction, and this leads to hydraBmia and increased capillary pressure, the arterial tension remaining unchanged. This augmentation of the capillary pressure in turn induces a flow of lymph from the blood vessels into the lymph spaces. The flow of lymph from the blood vessels is first, therefore, dimin- ished in amount by the presence of salt in the intestine and blood, and then increased again by the high capillary pressure. This interchange between the blood and lymph is continued, because as the salt is ex- creted by the kidneys and other excretory glands, a continual varia- tion in the osmotic pressure of both blood and lymph occurs. The details of the changes between the blood and lymph under the action of salt and water are still obscure, but there is no question that the absorption of either of these leads to an augmentation of the normal exchange of these fluids. In particular, it is still undecided whether the cells of the vessels possess a secretory function similar to that of the secretory glands, or whether the whole process may be attributed to variations of osmotic pressure and filtration. The changes in the blood and lymph are followed by an increased activity of the Excretory Organs. Thus the urine l is much augmented by the injection of salt solution into the blood, less so by the absorption of water or salt solution from the stomach and bowel. A good deal of discussion has been carried on in recent years as to the cause of the diuresis from salts and water, and some authorities hold that the presence of salt in excess in the blood stimulates the renal cells much in the same way as caffeine. But a more plausible explanation is that the greater volume of the blood, following the absorption of the fluid and the increased flow of lymph, results in an increase in the capillary pressure in the glomerulus and this in turn promotes the escape of fluid into the capsule. A more rapid flow through the tubules follows, and the glomerular secretion lies in them for a shorter time, so that there is less tendency for its constituents to be reabsorbed into the blood vessels ; the fluid reaching the ureters is accordingly increased and the dissolved salts and urea are also augmented ; those constituents which in ordinary circumstances are absorbed most readily by the epithelium of the tubules are increased more than the others, so that the chlorides, and the potassium and sodium of the urine rise much more than the urea, phosphates or sulphates even when the diuresis is due to the absorption of water. Any other diffusible body increases the urine in the same way as salt, and urea has therefore been suggested as a diuretic ; it differs from salt in the difficulty with which it is absorbed from the tubules of the kidney and this further retards the absorption of the fluid, so that urea may probably have a more powerful diuretic action than sodium chloride. Other secretions, such as the saliva, are increased by salt, and this f l The following explanation of the diuresis is based upon the theory that all the con- stituents of the urine are excreted by the glomerulus, and that some of them, notably much ot the fluid and the alkali chlorides, are reabsorbed in passing through the tubules. See Journ. of Physiol., xxvii. , p. 429; xxviii., p. ,431 490 INORGANIC SALTS, ACIDS AND BASES. not only by a reflex from the mouth, but also because some of the salt is excreted by the salivary glands. When very large amounts of isotonic salt solution are thrown into the blood, the organism may have difficulty in excreting it rapidly enough, and the tissues are therefore found to be swollen and redema- tous in some parts of the body. When salt solution is injected into the serous cavities or into the lymph spaces, absorption occurs in the same way as from the alimentary canal, except that in the case of the serous cavities osmosis seems to play a greater, and the other forces a smaller role, than in the stomach and intestine. The administration of large quantities of fluid, either as water or as dilute salt solution, might be expected to have some effect on the general Tissue Change, through the increased movement of the lymph flushing out the cells and leading to a more complete removal of the waste products. As a matter of fact, some increase in the nitrogen and sulphur eliminated in the urine has been observed under the use of large quantities of water, but it is impossible to estimate at present how far this may be due to the diuresis alone ; in any case the increase is not by any means so large as is often believed, as it only amounts to some 5 per cent., or less. Any salt solution causing an acceleration in the movement of the fluids of the body must tend to facilitate the excretion of the waste products in the same way, but some recent investigations indicate that in addition salt tends to lessen the proteid metabolism through acting directly on the cells ; this action is so slight, however, that the resulting fall in the nitrogen eliminated is concealed by the increase caused by the more complete flushing and diuresis. The amount of proteids and fats absorbed from the alimentary tract does not appear to be altered by the administration of large amounts of water (Edsall). Strong salt solutions injected into animals either hypodermically or intra- venously sometimes prove fatal, apparently from the withdrawal of fluid from the central nervous system. The symptoms in mammals are increas- ing lassitude and weakness, with augmented reflex excitability, tremors, and finally convulsions. The circulation is only slightly affected until just before death, when the blood-pressure falls suddenly. The red blood cells are found to be much shrunken, and according to Heinz, form thrombi in many vessels. Haemorrhages are found in different organs, the lungs are oadema- tous, and the intestinal mucous membrane is swollen and congested. The Salts of the Urine are increased by diuresis from any cause as has been stated ; both sodium and potassium are augmented but espe- cially the sodium which is present in larger proportions in the serum and therefore forms a larger constituent of the glomerular secretion. This increase in the sodium salts is of course particularly marked when diuresis is induced by common salt, but when potassium salts increase the urine, the sodium also generally predominates in it and this would eventually lead to the loss of all the sodium in the blood of herbivora, whose food contains large quantities of potassium ; but after a certain SODIUM CHLORIDE AND WATER. 491 amount of sodium has been lost, potassium causes no further excretion so that the tissues apparently protect themselves from the total loss of sodium chloride, which would be fatal to them. Bunge states that in both man and animals a diet lich in potassium causes an appetite for common salt, while a diet which does not contain an excess of potash, does not develop this desire. Thus herbivorous animals and agricultural peoples seek for salt, because vegetable foods contain large quantities of potassium, while the carnivora and the hunting peoples require no salt and often have a distaste foi it, owing to their food containing a larger relative proportion of sodium salts. This instinctive appetite he regards as a means by which nature protects the tissues from excessive loss of sodium. Some doubt has recently been thrown on this explanation of the desire for salt by Lapicque, who discovered some African races living on vegetable sub- stances alone, and using the ashes of the plants, which contain more potas- sium than sodium, as civilized peoples use ordinary salt. He holds, there- fore, that salt is merely of value as a flavoring agent. Therapeutic Uses. Water and salt are rarely or never prescribed as such, but are used to a very large extent in medicine, and great virtues have been ascribed to them in a number of pathological conditions. They are used for their local action, and for the supposed alterations in the tissue-change and in the excretions produced by them after their absorption into the blood. In general, patients are sent to watering places and baths, and the success of the treatment is to a considerable extent due to the climatic conditions, the change in the habits of life, the dietetic treatment, and the rest from everyday occupations. At the same time the drinking of large quantities of weak salt solutions, and the constant bathing in somewhat irritating fluids, may exercise a therapeutic action in many cases, and may at any rate aid the hygienic conditions. Whether the water contains salt or not, it must be remem- bered that in bathing the action is a purely local one, for neither the salt nor the water is absorbed. The slightly irritant effect on the skin may, however, improve its circulation and nutrition, and thereby be efficacious in some skin diseases. By continued use, the sensitiveness of the skin vessels to heat and cold may also possibly be deadened. Remarkable effects on the tissue change have been alleged to be pro- duced by bathing in strong salt solutions, owing to their counter- irritant action. For example, the excretion of urea and the oxidation in the body are often said to be much increased, but these results have not been confirmed after further experience. Special baths are very frequently recommended for some diseases, but it must be remembered that the action is due to the salt-action ; the greater the concentration, the greater is the effect on the skin, and it is of no importance which of the neutral salts is in the solution, or whether small traces of iron or other metals are present ; alkaline baths are more stimulant than others. In diseases of the stomach the drinking of large quantities of water or of weak salt solutions may also be beneficial. The action is similar to that on the skin a mild irritation, owing to the swelling up of 492 INORGANIC SALTS, ACIDS AND BASES. the more superficial cells of the epithelium and the increased move- ment of the fluid in them and in the deeper layers. In some cases of insomnia hot water sometimes causes sleep, probably by causing dila- tation of the gastric vessels, and thereby withdrawing the blood from the brain. In many diseases in which the symptoms point to a disorder of the metabolism, water and salt solutions are advised. Thus gout and rheumatism are frequently treated by sending the patients to watering places, on the theory that the tissues are washed out thoroughly, and the waste products thus removed. As a matter of fact, the more recent work in this direction shows that large quantities of water and dilute salt solutions have little or no effect on the uric acid excretion, which was formerly believed to be much diminished. This fact does not necessarily involve the inference that the treatment is erroneous, for it is now generally recognized that gout is not really due to the failure of the uric acid excretion. Many cases are unquestionably benefited by the springs, although it may be questioned how much of the improvement is due to the water taken, and how much of it ought to be ascribed to the changed conditions of life. The bath treatment has been recommended for numerous diseases in which the salt and water could not possibly have any beneficial action, and in which the remedial agent is the climate, and perhaps the faith of the patient in the water. Belief in the healing power of cer- tain natural waters is one of the most ancient of all therapeutic theories, is found among altogether uncivilized peoples, and has been incorporated in many religions. It is not to be wondered at that in some nervous disorders the faith of the patient and auto-suggestion perform some marvelous " cures." In obesity the drinking of some waters, such as that of Kissingen or Homburg, has been advised. These waters contain from 0.21.4 per cent, sodium chloride, and it seems very doubtful if they have any effects in themselves ; many hold that the benefits accruing from the treatment are really due to the hygienic measures followed, and that the waters play only an insignificant role. Salt in solid form or in strong solution is used occasionally as an emetic in cases of emergency, as in poisoning, and generally produces vomiting rapidly, owing to the irritant action on the stomach. In nitrate of silver poisoning it arrests the corrosive action by the forma- tion of the insoluble silver chloride. Salt solution is often used instead of water in enemata, and when con- centrated possesses an irritant action on the bowel, producing peri- stalsis. Strong solutions are sometimes thrown into the rectum to destroy round worms. Isotonic salt solutions (0.6-0.9 per cent.) are often administered when the body has lost much fluid, as they are rapidly absorbed and are devoid of irritant action ; thus in haemorrhage these solutions are injected subcutaneously, intravenously, or per rectum. A rapid SODIUM CHLORIDE AND WATER. 493 improvement in the circulation follows, and this has given rise to the erroneous opinion that such saline infusions stimulate the heart directly as well as by the mechanical effect of the increase in the fluids of the body ; this theory has led to infusions being made in weakness of the heart from other causes than hemorrhage. Some of the symp- toms of cholera are believed to be due to the loss of fluid, and these are said to be relieved by the injection of salt solutions, though the mortality does not seem materially altered. The intravenous and sub- cutanous injection of salt solution has been recommended in uremia and similar intoxications, with the idea of washing out the poisons through the kidneys ; the same results can often be obtained by drink- ing large quantities of water. There is still some question as to whether the infusion of salt solution is really remedial in loss of blood, and the latest investigator of the matter, Feis, comes to the conclusion that it is of little or no benefit. The hypodermic injection of large quantities of isotonic salt solution is" said by Bieruacki to have effects which only pass off in some 68 days in animals. The blood was at first much diluted, but afterwards became very concentrated and after a few days a considerable number of the red cells were found in a state of disin- tegration, and the haemoglobin thus liberated was distributed through the plasma until it was finally excreted in the urine. The animals did not seem to suffer from the treatment, but his results indicate that the injection of large quantities of salt solutions is by no means the harmless proceeding which it is generally believed to be. Isotonic salt solutions are used in surgery to wash out the peritoneal cavity, which would be injured by distilled water. PREPARATIONS. Sodii Chloridum (U. S. P., B. P.), common salt. Aqua (U. S. P.). Aqua Destillata (U. S. P., B. P.). BIBLIOGRAPHY. See Salt-Action (page 489) and Saline Cathartics. Heidenhain. Pfliiger's Arch., xlix., p. 209; Ivi., p. 579. Starling, etc. Journ. of Physiol., xvi., xvii., xviii., xix. Cohnstein. Pfliiger's Arch., lix., Ixii., Ixiii. Virchow's Arch., cxxxv., p. 514. Mendel. Journ. of Physiol., xix., p. 227. Orlow. Pfliiger's Arch"!, lix., p. 170. v. Limbeck. Arch. f. exp. Path. u. Pharm., xxv., p. 69. Dreser. Ibid., xxix., p. 303. Reichmann. Ibid., xxiv., p. 78. Munzer. Ibid., xli., p. 74. Loeb. Amer. Journ. of Physiol., iii., pp. 327, 383, 434. Pfl tiger's Arch., Ixxxviii., p. 68 ; xcvii., p. 394. Gabriel. Ztschr. f. Biol., xi., p. 554. Heinz. Virchow's Arch., cxxii., p. 100. Bunge. Lehrbuch der phys. u. path. Chemie, 2d ed., p. 107. Ztschr. f. Biologie, xli., p. 484. Grawitz. Zts. f. klin. Med., xxii., p. 417. Ludwicj. Centralbl. f. inn. Med., 1896, Nos. 45 and 46. Weber. Ergeb. d. Phys., iii., 1, p. 268 (metabolism). Loeb, Mathews, Zoethout, Lillie, etc. Amer. Joum. of Physiol., iii.-xi. (antagonistic action of salts). 494 INORGANIC SALTS, ACIDS AND BASES. Feis. Virchow's Arch., cxxxviii., p. 75. Biemac/ci. Ztschr. f. klin. Med., xix., Suppl., p. 49. Straub. Ztschr. f. Biologie, xxxvii., p. 527 ; xxxviii., p. 537. Magnus u. Gottlieb. Arch. f. exp. Path. u. Pharm., xliv. and xlv. Lenhartz. Deutsch. Arch. f. klin. Med., Ixiv., p. 189. Leon/acker. Mittheil. a. d. Grenzgebiete, vi., p. 321. Taylor, Frazier, Edscdl. Pepper Laboratory Keports, Philadelphia, 1900, pp. 356, 368. Soilmann. Arch. f. exp. Path. u. Pharm., xlvi., p. 1. II. POTASSIUM SALTS. The effects of potassium in the organism can best be studied by ad- ministering the chloride, as the Cl ion is practically devoid of action and the symptoms induced by potassic chloride must therefore be due either to the " salt-action " or to the potassium. The salt-action can be discounted by comparing the symptoms with those of an isotonic solution of sodium chloride, and when this is done it is found that potassium has a distinctly poisonous action, which is chiefly manifested in depression of the central nervous system and of the heart. In the frog the central action is shown by the spontaneous move- ments becoming weak and slowly performed, and by their completely disappearing much earlier than in sodium chloride experiments. In mammals the chief nervous symptoms are great muscular -weakness and apathy. The respiration becomes rapid and labored, probably from the anaemia of the centres, and death is often preceded by weak as- phyxial convulsions. The depression of the heart is shown in the frog by weakness, slow- ness and irregularity when chloride of potassium is injected subcu- taneously, but is more clearly demonstrated by the rapid failure of an excised heart when a chloride of potassium solution is perfused through it. An isotonic solution of common salt also brings the heart to stand- still after a time, but potassic chloride acts very much more quickly, and, in fact, the former may restore the heart beat after it has been stopped by potassium, which proves conclusively that the latter has a specific poisonous action in addition to any salt-action. Ringer, how- ever, found that the beat of the frog's heart perfused with a solution of common salt was not so satisfactory as that of one perfused with the same solution to which some potassic salt had been added, because, as has been already mentioned, the proteids of the heart must contain potassium, and when this is substituted by sodium, as is the case when there is no potassium in the perfusion fluid, the muscle becomes in- capable of normal contraction. (See Calcium.) The mammalian heart is also injured by the action of potassium when the salt is administered in large quantities, as is shown by the pulse becoming much slower and weaker and by a sudden fall of blood- pressure ; an acceleration of the pulse is often observed at first. The poisonous action of potash on the heart has given rise to exaggerated apprehensions of the danger of using its salts in therapeutics, and it may therefore be noted that potassium has practically no effect on the heart when given by the stomach, and that very much larger quantities of potash are taken daily in the food by thousands of persons than are POTASSIUM SALTS. 495 ever prescribed in medicine. Bunge estimates the amount of potash in the food of some classes at 50-100 grms. (1J-3 oz.) per day. The absence of effects from the potassium ion when the salts are taken by the mouth is due to their rapid excretion in the urine. The failure of the heart is the cause of death in mammals when potassium salts are injected into a vein, the respiration and the reflexes often persisting for a few seconds afterward. According to Braun, potassium salts cause a transient contraction of the vessel walls when they are injected directly into the arteries. Potassium has some action on muscle in the frog, the contraction seeming to be somewhat greater in height, though shorter in length, and there being less tendency to contracture. Muscle exposed in a solution of potassic chlo- ride dies very much sooner than in an isotonic solution of sodium chloride. Chloride of potash has also some depressant action on the peripheral nerves, for they lose their irritability rapidly when they are exposed to its solutions. A concentrated solution applied to an exposed nerve causes con- tractions of the muscles which are supplied by it, but these are weaker and last a much shorter time than those elicited by a similar solution of common salt. This is explained by the depressant action of the potassium opposing the irritation which it induces through its salt-action. This effect on the nerves has been used by Pohl to explain a curious observation made by Nothnagel, who found that a strong solution of chloride of sodium ap- plied to the peritoneal surface of the rabbit's intestine, causes a local con- traction, followed by an upward peristaltic wave, while a similar solution of a potassium salt induces only local contraction. Pohl supposes that in the case of the sodium salt the peristaltic wave is caused by nerve stimulation, while the potassium depresses the nerve so much that it is unable to carry the impulses, and the contraction therefore remains local. The absorption of potassium salts is followed by the same changes in the movement of the fluids of the body as have been described in the case of sodium chloride (page 489). This generally results in diuresis with an in- crease in the potassium and the sodium and chloride in the urine. It is often stated that the potassium salts induce a more marked increase in the urine than those of sodium, but this is not based on any satisfactory measurements ; another statement which requires confirmation, is that strong solutions of po- tassic chloride are more irritating to the stomach and also in the subcutane- ous tissues, than those of sodium chloride ; this would indicate that potassium has a specific irritant action apart from its salt-action, which is not unlikely, although it cannot be said to have been demonstrated satisfactorily as yet. BIBLIOGRAPHY. See also Salt-action (p. 485) and Sodium Chloride (p. 493). Bunge. Pfliiger's Arch., iv., p. 235. Handbuch der physiol. Chem., p. 107. Braun. Pfliiger's Arch., ciii., p. 476. Martin. Amer. Journ. of Physiol., xi., p. 370. Pohl. Arch. f. exp. Path. u. Pharm., xxxiv., p. 95. Limbourg. Ibid., xxiv., p. 342. Ringer. See the bibliography given under Calcium. DogieL Centralbl. f. d. med. Wiss., 1892, p. 354. Brunton and Cash. Phil. 'Trans. Roy. Soc., 1884, Part 1, p. 197. Lithium, Caesium, Rubidium. In regard to the action of the rarer alkalies, Lithium, Cesium and Rubid- ium, 1 comparatively little is known. They seem to have some effect in de- 1 The still rarer metals Yttrium, Erbium, Beryllium, Didymium and Lanthanum have scarcely received examination except at the hands of Brunton and Cash, and are not of sufficient importance to require further mention here. 496 INORGANIC SALTS, ACIDS AND BASES. pressing the spinal cord in the frog, but it is uncertain whether this is, like the action of sodium chloride, merely due to the presence of large quantities of salts in the body, or whether they have a specific action on the nerve cells. Lithium seems to have some further depressant action on the motor nerves, and to weaken the muscular contraction. It acts much less powerfully on the mammalian heart than potassium, but has some effect in weakening it. Its chief effects are exercised in the alimentary tract, for gastro-enteritis and extravasations of blood into the stomach and bowel are induced by its sub- cutaneous or intravenous injection and these are the cause of death in fatal poisoning in animals. Such violent effects are less easily elicited by the ad- ministration of lithium by the mouth, though vomiting and purging have been caused in animals by this method also, and disturbance of the alimentary tract has sometimes followed lithium treatment in man. Some of the lithium is excreted in the bowel, and in this respect this metal appears to form a contrast to potassium and sodium and to resemble rather the group of alkaline earths. Rubidium seems to act on the frog's heart and on muscle cells in much the same way as potassium. Csesium resembles lithium in causing inflammatory reactions in the alimentary tract, leading to vomiting and diarrhoea, when it is injected hypodermically or when large doses are given by the mouth. It is partly excreted along the ali- mentary tract in mammals. In the frog it induces weakness of the muscles and paralysis. BIBLIOGRAPHY. Dietrich u. Harnack. Arch. f. exp. Path. u. Pharm., xix., p. 153. Brunton and Cash. Phil. Trans. Roy. Soc., 1884, p. 197. Binet. Comptes rendus de 1' Academic, cxv., p. 251. Eichet. Arch. de. Physiol., 1886, i., p. 101. Trav. d. Laborat. de Physiol., 1893, ii., p. 398. Blumcnthal. Pfliiger's Arch., Ixii., p. 513. Winkler. Ibid., Ixxi., p. 395. ^ Good. Amer. Journ. Med. Sciences, cxxv., p. 273 (lithium). Hanford. Amer. Journ. of Physiol., ix., p. 214 (caesium). III. AMMONIUM. Although ammonium is not a metal, its behavior in the body resem- bles in many points that of the fixed alkalies, and it may therefore best be studied along with them. The ordinary solutions of ammonia, and the gas itself are possessed of powerful irritant properties, and its general action can be determined only by the examination of those of its salts in which, as in ammonium chloride, the effects of the anion can be neglected. The action of chloride of ammonium is due to the specific action of the base and to the salt-action. Action. Its most striking effect is the stimulation of the Central Nervous System, which is induced when it is injected subcutaneously or intravenously. The reflex irritability is much increased, and this may be followed by tetanic convulsions both in frogs and mammals. These convulsions persist after division of the cervical spinal cord and destruction of the medulla oblongata and brain, and are evidently caused by changes in the spinal cord, similar to those met with in strychnine poisoning. According to Yourinsky, the increased reflex and the convulsions are preceded by a short stage of depression in the frog and pigeon, but this depression is not observed when the parts of the central nervous system above the cord are destroyed in the frog, or when the cerebrum is removed in the pigeon. He holds that the AMMONIUM. 497 brain is first stimulated, and that this action inhibits the reflexes, but that as the stimulation passes downwards, the spinal cord is acted on in turn and the reflexes are exaggerated. The medullary centres are also involved, for the respiration very often ceases for a moment, and then becomes very much accelerated, and in some instances deeper. The cause of the altered breathing is a stimulation of the respiratory centre ; the preliminary pause is attributed by some to action on the vagus ends in the lungs, but this is denied by others, and it seems pos- sible that it is due to excessive stimulation of the respiratory centre. The blood-pressure rises from contraction of the peripheral arterioles, induced by stimulation of the vaso-motor centre, while the heart is sometimes slowed from increased activity of the inhibitory centre, but is said to be accelerated in other cases ; whether this arises from action on the cardiac muscle or on the accelerator centre is still unknown. During the convulsions, the respiration is arrested and the blood- pressure becomes extremely high* If large enough quantities be in- jected, the stimulation is followed by paralysis of the central nervous system and the animal dies of asphyxia, but if artificial respiration be carried on it recovers rapidly, from the salt being changed to an inac- tive substance in the tissues. In the frog ammonium chloride tends to paralyze the terminations of the Motor Nerves, but little or no such action is met with in mammals. This marked curara-like action differentiates the ammonium tetanus of the frog from that seen under strychnine, as the spasms last a shorter time, and soon become weaker from the impulses failing to reach the muscles through the depressed terminations. The Muscles themselves are also acted on by ammonium in much the same way as by potassium, although in the case of ammonium a preliminary stage of somewhat augmented irritability has been observed by some investigators. Am- monium chloride is generally credited with acting on the Secretions of the stomach and of the bronchial mucous membrane, which it is said to render more fluid and less tenacious, and at the same time to increase considerably. 1 No explanation of this effect on the mucous secretion has been offered, and ammonia does not seem to be excreted by the lungs, nor has it been found in the bronchial secretion. Ammonium salts penetrate most cells of the body more freely than the salts of the fixed alkalies, and solutions of ammonium chloride are therefore absorbed more rapidly from the stomach and intestine than those of sodium or potassium chloride. They permeate into the blood cells with still greater freedom, and, in fact, solutions of the chloride of ammonium meet with little more resistance in entering the red blood corpuscles than does distilled water. If ammonium be combined with a non-permeating ion it penetrates the blood cells or the intestinal epithelium with difficulty, however, so that the sulphate of ammonium is slightly cathartic, although less so than the sulphates of the fixed alkalies. (See Saline Cathartics.) The epithelium of the lungs appears 1 Rossbach states that the injection of the chloride into the vein of an animal lessens the bronchial secretion. 32 498 INORGANIC SALTS, ACIDS AND BASES. to be impermeable by the ammonium ion, so that when ammonia is inhaled it does not reach the blood, and when it is absorbed from the alimentary tract it does not appear in the breath (Magnus). When ammonium salts are taken by the mouth, they have little or no tendency to cause symptoms from either the central nervous system or the heart. No case is known in which convulsive attacks could be shown to be due to the direct action on the central nervous system in man, and it is very doubtful whether the circulation is aifected at all. In some cases of poisoning with ammonium hydrate, convulsions have occurred, but these seem to be due to the violent local action of the caustic alkali. The chloride of ammonium may induce irritation and vomiting when taken in large quantities into the stomach, but only through its action as a salt. Ammonium is changed to urea in the body and is Excreted in this form in the urine. This transformation, which probably takes place in the liver chiefly, proceeds very rapidly, so that considerable quantities of some salts may be injected slowly into a vein without inducing any symptoms whatever. The urea in the urine would therefore tend to be increased by ammonia if other factors were not involved, and as a matter of fact this occurs in the herbivora. In carnivorous animals and in man, on the other hand, some of the salts of ammonium increase the ex- cretion of urea, while others apparently increase the ammonium salts in the urine. Thus the carbonate or acetate of ammonium is excreted as urea, while the chloride appears to be excreted unchanged. This differ- ence in the behavior of the ammonium salts is more apparent than real, however. As a matter of fact the ammonia is excreted as urea in each case, but the acid with which it is in combination may conceal this. In the case of the carbonate no acid is freed, and the same is true of the acetate, which is oxidized to the carbonate in the tissues. When, how- ever, urea is formed from ammonium chloride, hydrochloric acid is lib- erated in the tissues and would act as a poison, were it not neutralized at once by ammonia being formed in the tissues themselves. It is then ex- creted by the urine in combination with this freshly formed ammonia, 1 while that with which it was formerly combined appears as urea. The formation of ammonia in the tissues, however, withdraws some nitrogen which would ordinarily have formed urea, so that the net result is that the urea excretion is little changed, while the ammonia of the urine is much increased. The carnivora therefore neutralize the hydrochloric acid with freshly formed ammonia. The herbivora on the other hand neutralize it with fixed alkali, so that the administration of ammonia always increases the urea excreted by them, while little or no ammo- nia appears in the urine ; at the same time the fixed alkalies of the blood tend to become neutralized, and this may give rise to serious symptoms. (See Acids.) The urine is often increased by the exhibition of ammonium salts, but not always. It is to be noted that, while the alkaline salts of the fixed 1 In some cases apparently the hydrochloric acid is not excreted in this way at once but goes to increase the acidity of the gastric juice. AMMONIUM. 499 alkalies render the urine less acid or even alkaline, ammonium salts have no such effect, because they are excreted as urea. In birds and reptiles, ammonia is apparently excreted as uric acid. The Substituted Ammonias of the methane series, such as methylamine, and some of those of the aromatic series resemble ammonia in their general effects, but the stimulation of the central nervous system is not often so marked a feature. In general terms, those compounds in which one hydro- gen atom is substituted, tend to cause greater nervous stimulation than those in which two or three such substitutions are made, while this action is again more prominent in those in which four alkyl groups are combined with the nitrogen. In addition, most of these compounds seem to have a more depres- sant action on the central nervous system afterwards than ammonia, and they all tend to weaken and eventually paralyze the terminations of the motor nerves. The ammonium bases formed from the natural alkaloids appear to have less action on the central nervous system, but act like curara on the termina- tions of the motor nerves. (See page 260.) PREPARATIONS. Ammonii Chloridum (U. S. P., B. P.) (NH.C1), 0.3-1 G. (5-15 grs.), in solution. Trochisci Ammonii Chloridi (U. S. P.), each containing 0.1 G. (2 grs.) of ammonium chloride with 0.25 G. (4 grs.) of liquorice extract and some syrup of Tolu. Therapeutic Uses. The chloride is prescribed chiefly for its effects on the respiratory mucous membranes, and is a very common constit- uent of expectorant mixtures for bronchitis and catarrh. The lozenge is often used for sore throat, and chloride of ammonium solutions are occasionally inhaled or sprayed into the throat. It has also been pre- scribed in gastric catarrh with benefit in some cases, but whether this is due to its acting on the mucous secretion, or to its increasing the acidity of the gastric juice is unknown. Ammonium chloride and the chloride of trimethylammonium were at one time advised in rheumatism, but have proved useless in this disease. BIBLIOGRAPHY. On the Action of the Ammonium ion. Lange. Arch. f. exp. Path. u. Pharm., ii., p. 364. Feltz et Ritter. Journ. de 1'Anat. et de la Physiol., 1874, p. 326. Funke. Pfluger's Arch., ix., p. 416. Binz. Centralbl. f. klin. Med., 1888, p. 25. Yowrinsky. Arch. d. Sciences biolog. , iii., p. 260. Bossbach. Festschr. zur dritten Saecularfeier, Wiirzberg, 1882, i., p. 85. Formanek. Arch, internat. de Pharmacodyn., vii., p. 229. Magnus. Arch. f. exp. Path. u. Pharm., xliv , p. 100. On the fate of ammonia in the body. Schmiedeberg. Arch. f. exp. Path., viii., p. 1. Hallervorden. Ibid., x., p. 125. Coranda. Ibid., xii., p. 76. Knieriem. Zeitschr. f. Biol., x., p. 263. Salkoivski. Zeitschr. f. physiol. Chem., i., p. 1. Marfori. Arch. f. exp. Path. u. Pharm., xxxiii., p. 71. Rumpf u. Kleine. Zts. f. Biol., xxxiv., p. 65. Pohl u. Munzer. Arch. f. exp. Path. u. Pharm., xliii., p. 28. 500 INORGANIC SALTS, ACIDS AND BASES. On the action of substituted ammonias. Brunton and Cash. Phil. Trans. Eoy. Soc., 1884, i., p. 197. Nebelthau. Arch. f. exp. Path. u. Pharm., xxxvi., p. 451. IV. BROMIDES. It was formerly widely believed that the bromides had DO further action than the chlorides, and that any effects observed from potassium bromide were due to the potassium ion, the bromide ion being indif- ferent. There is now no question, however, that the bromides have distinctive effects, for the bromides of potassium, sodium, lithium, and other metals induce changes in the central nervous system, which are not elicited by the chlorides. At the same time the bromide action is comparatively weak, and the basic part of the salt has therefore con- siderable influence on the action. Symptoms. The bromide of potassium is the salt most generally used, and its action has been more carefully described than that of the other bromides. In the Alimentary Tract it acts in the same way as the chloride of sodium, possessing a bitter salt taste and inducing salivation and thirst, and in large quantities, irritation of the stomach, nausea and vomiting. Occasionally diarrhoea has been observed from concen- trated solutions reaching the intestine. General Symptoms. Apart from these results of local irritation, the first symptom is often a dull, heavy headache, with a feeling of lassi- tude, fatigue, disinclination for exertion, mental or physical, and often muscular weakness. Thought is slow and confused, the memory is indistinct, ideas are put into words with difficulty and the speech is accordingly slow and hesitating. External objects and movements are perceived, but arouse no interest in the patient, and very often this state of apathy passes into drowsiness and sleep. The bromides, how- ever, have not the sleep-compelling power of morphine or chloral, and the sleep is never very deep and is not refreshing, the patient some- times feeling dull and unfit for exertion after it, and some mental con- fusion often persisting for several hours after awaking. The reflexes are much depressed by large doses of bromide, so that touching the back of the throat does not induce nausea, although the sensation of touch may persist. The mucous membranes of the genito-urinary tract are also less sensitive, or rather their irritation is less liable to set up reflex movements. After very large doses of the bromides the conjunctiva may sometimes be touched without causing winking, and lessened sensation in the skin has been noted in some cases. The pulse is slow and weak after large doses and the respiration is also less active. An increase in the urine is often observed. Acute fatal poisoning with bromides has seldom or never occurred in man, but after enormous doses prolonged sleep or stupor has been seen, and confusion and apathy lasting for several days. When bromide is given repeatedly in large doses, a series of symp- toms is often induced to which the name of Bromism has been applied, BROMIDES. 501 It occurs much more rapidly in some persons than in others, and may suddenly appear after the patient has been taking the drug for months without any untoward results. The commonest symptoms of bromism are akin eruptions of various kinds, very often commencing as acne of the face. In severe cases the pustules of acne may coalesce and form small abscesses, which are followed by ulcers. In other cases the skin affection partakes rather of the nature of a localized blush or erythema, and sometimes copper-colored blotches have been observed. Some dis- turbance of the digestion and loss of appetite is often met with from the local action of large quantities of the salt on the stomach. Affections of the respiratory passages are not produced so often by the bromides as by the iodides, but have been met with and consist in an increased secretion of mucus by the bronchial and nasal epithelium. The mental symptoms are merely exaggerations of those observed after one large dose. The memory is especially defective, sometimes sudden lapses occurring, sometimes a general inability to remember the most recent events being met with. The patient is indifferent to his surroundings, speaks slowly and stammers, mispronounces ordinary words, or misses several words out of a sentence. The gait is uncertain and tremor often accompanies any movement, the expression of the face is stupid and apathetic, and the eyes are heavy and lack lustre. These symptoms generally disappear on the withdrawal of the drug, but in his reduced condition the patient is of course liable to fall a victim to infectious disease, and in a number of cases of chronic bromide poisoning the immediate cause of death has been an attack of bronchitis or pneumonia. Action. The effects of the bromides on animals have been the sub- ject of a large number of researches, but these have not been attended with success in most cases, because the investigators have almost always used the bromide of potassium. The action here is complicated by the potassium action as well as by the salt-action, and these are often sufficient to obscure the slight depression of the brain which is the really characteristic effect of the bromide ion. In the frog, for example, potassium chloride is capable of inducing depression of the central nervous system, and a certain amount of stupor is induced by the salt action of chloride of sodium. The slightly greater depression induced by the bromide may well be overlooked, therefore, and many investigators have concluded that the bromide ion is as inactive as the chloride. The typical bromide action may be induced with greater clearness in mammals by the use of sodium bromide in repeated doses, and in dogs symptoms of depression and imperfect coordination have been observed, and sometimes stupor and death from failure of the respiration. The most characteristic action, however, is obtained from the administration of the drug to patients, as the affection of the cen- tral nervous system is so slight after all but extreme doses, that in order to produce distinct symptoms in the less sensitive brain of the dog, quantities must be used which entail the additional complication induced by salt-action. 502 INORGANIC SALTS, ACIDS AND BASES. The irritation of the throat and stomach, the nausea, vomiting, and rarer diarrhoea must be attributed for the most part to the action of the salt in withdrawing fluid from the mucous membranes, and may be avoided by the use of dilute solutions and by their administration when the stomach is full. The depression and other mental symptoms are due to a direct action on the Central Nervous System. Albertoni found that the irritability of the motor areas of the dog's brain was very distinctly reduced by the administration of bromides, and in particular that a stimulus which normally would have spread over a wide area and given rise to an epileptiform convulsion, caused only localized contractions after bro- mides, while convulsive poisons entirely failed to act. Loewald found some psychical processes, such as those involved in the addition of numbers, uninfluenced by bromides, while a series of figures could be learned by rote only with great difficulty ; he therefore considers that the action is limited to certain definite functions. The reflexes are also reduced very considerably by bromides, and according to many observers this occurs in the frog before the spontaneous movements cease. This is explained by the passage of impulses from the sensory to the motor cells of the cord being interrupted, while the connection between the cerebral centres and the motor cells of the cord is main- tained intact. The reflexes in man are prevented or retarded also, the most striking instance being the absence of reflex nausea when the back of the throat is touched. The other reflexes are also reduced, especially those of the genital organs, those of the conjunctiva being less affected. While reflex movements cannot be elicited, the sensa- tion often remains unimpaired, but after large doses a more or less complete anaesthesia is said to be produced. This anaesthesia extends to the skin when very large quantities are administered, and the cuta- neous nerves are said to be rendered somewhat less acutely sensitive, when comparatively small doses are taken. The depression of the spinal reflexes effected by the bromides ren- ders them antidotal to strychnine, which induces convulsions only when given in much larger quantities than are usually necessary. In addition to the ordinary reflexes, some special functions are de- pressed by the bromides. Thus the respiration becomes slower, and the sexual instincts are depressed or entirely suspended in many cases. Whether the latter is caused by action on the spinal cord or on the cerebral cortex is unknown. The action on the central nervous system is due to the bromide only, and not to the base with which it is combined. Thus, it may be elicited by the bromides of potassium, sodium, lithium or ammonium, while it is not induced by their chlorides. The bromide ion is not very poisonous to Nerve and Muscle, but it is not so nearly indifferent to them as the chloride ion, although no effects are elicited unless the bromide is applied directly to the exposed mus- cle or nerves. The Cardiac Effects, when present, arc caused by the potassium com- BROMIDES. 503 ponent only, and are not elicited by the bromides of sodium and am- monium. The vessels of the pia mater are often found contracted from the action of bromides, and this has been supposed to account for the depression. It is probable, however, that this anemia of the brain is analagous to that observed in sleep and it may therefore be the result and not the cause of the depression. The mental disturbance observed in bromism is so nearly related to that seen after a single large dose, that it is unnecessary to enter into any explanation of it here. The Skin Eruptions have usually been attributed to the excretion of bromide through the cutaneous glands, and seem to arise in the great majority of cases from the glands, and in fact generally remain con- fined to them. Bromide has been found in the acne pustules, and it is quite conceivable that it may act as an irritant here, especially when the secretion becomes acid from decomposition. The Temperature of animals is often said to be reduced by the bro- mide ; this may be explained by the lessened movement. Excretion. The bromides are rapidly absorbed by the mucous membranes, and some bromide reaction can be obtained from the urine a few minutes after they have reached the stomach, but the great mass of the drug is very slowly excreted. When the treatment is continued, the bromide therefore tends to accumulate in the body, but the pro- portion excreted rises with the increase of the salt in the blood, until an equilibrium is reached, exactly as much bromide appearing in the urine as is absorbed from the stomach. The excretion continues after the treatment is discontinued, and the drug is found in the urine for one or two months afterwards. When the body is thus saturated with bromides, some of the chloride combinations are replaced by them ; for example, Nencki found that the acid secreted by the stomach might contain more hydrobromic than hydrochloric acid. The substitution of bromide for chloride may be the cause of some of the symptoms of bromism ; one consequence is that the chlorides released from their combinations, are excreted in much larger quantity than usual in the urine. The nitrogenous metabolism does not seem to be affected, but in some cases a considerably smaller amount of phosphates appears in the urine. This has been supposed to be related to the action of bromides in lessening the mental activity, but is not by any means a constant effect. The bromides seem to be distributed in the body very much in the same proportion as the chlorides, being most largely found in the blood serum, while the brain and spinal cord contain them in com- paratively small proportion. The bromides are excreted mainly in the urine, but traces occur in the perspiration and milk, and some cases of bromism in children have been recorded as due to their absorbing the bromide thus ex- creted by the nurse. In chronic poisoning the breath very often has a disagreeable odor, which has been attributed to bromine or some of its volatile organic compounds being excreted by the lungs, but noth- ing is known with certainty regarding it. Bromine has also been 504 INORGANIC SALTS, ACIDS AND BASES. found in the hair after the prolonged use of bromides, and is supposed to exist in organic combinations here. The hydrobromic acid secreted into the stomach in bromism is probably all reabsorbed in the intestine. Bromide of Sodium differs from bromide of potassium chiefly in the absence of any changes in the heart or in the muscles exposed to its solution. The central nervous system also seems somewhat less de- pressed, because the potassium in itself has some effect, while the sodium ion is indifferent. Bromide of Ammonium owes most of its action to the bromide ion, unless when it is given in large quantities, when, according to several observers, the convulsive action characteristic of ammonium is devel- oped in animals. Smaller doses are followed by lethargy and weak- ness in animals, and in man the effects are practically identical with those of sodium bromide. Lithium Bromide has not been so largely used as the others, and is liable to cause digestive disturbances from the lithium action (see p. 495). Hydrobromic Acid possesses the characteristic bromide action after absorption, but has the local action of an acid and is consequently more irritant than the other members of the series. Strontium and Calcium Bromides seem to resemble the others in their general action and are said to disturb the digestion less. At the same time calcium and strontium salts are generally absorbed more slowly by the intestine than those of the alkalies. PREPARATIONS. POTASSII BROMIDUM (U. S. P., B. P.) (KBr), 1-4 G. (15-60 grs.). SODII BROMIDUM (U. S. P., B. P.) (NaBr), 1-4 G. (15-60 grs.). Ammonii Bromidum (U. S. P., B. P.) (NH 4 Br), 1-2 G. (15-30 grs.). Liihii Bromidum (U. S. P.) (LiBr), 1-2 G. (15-30 grs.). Calcii Bromidum (U. S. P.) (CaBr 2 ), 2-4 G. (30-60 grs.). Strontii Bromidum (U. S. P.) (SrBr 2 ), 2-4 G. (30-60 grs.). Acidum Hydrobromicum Dilutum (U. S. P., B. P.) contains comparatively little bromide, as it is only a 10 per cent, solution in water, so that a gramme of bromide of potash contains as much bromine as about 7 grammes of the dilute acid. 6-12 c.c. (J-3 fl. drs.) (B. P., 15-60 mins.). The bromides are all colorless crystalline bodies without odor but with a saline, bitter taste, and are very soluble in water They are almost always prescribed in solution and ought to be taken diluted with a considerable amount of water in order to avoid the irritant action on the stomach. The prescription may be flavored with syrup and with some of the volatile oil preparations. The large doses of the bromides render their hypodermic in- jection inadmissible, as concentrated solutions provoke pain and irritation in the subcutaneous tissues. A number of other bromide combinations are used in therapeutics, such as the hydrobromate of quinine, but here the bromide ion is present in very small quantity compared with the alkaloid, and in the doses used in ther- apeutics has no appreciable effect. In monobromated camphor the bro- mine is present in a different form and no bromide ion is liberated, so that the action of the metallic bromides cannot be compared with it. As a matter of fact, the bromine in this compound seems to have little or no effect. Therapeutic Uses. The bromides are used chiefly in the treatment of epilepsy, in which they cannot be replaced by any other drug, and BROMIDES. 505 the prognosis of which has been entirely changed since their introduc- tion. In a few cases the bromide treatment is said to cure epilepsy the attacks do not return after the treatment is stopped but this is exceedingly rare ; in others the bromides have no effect, but in the great majority of cases (90-95 per cent.) the number of attacks is much smaller, or the patient may be entirely free from them as long as the treatment is persevered with, although they return as soon as it is tiven up. Very often no improvement is observed during the first i\v days, until the tissues have become saturated with bromide, but in other cases the spasms disappear immediately. The bromide of potas- sium is more commonly used than the others, and the general impres- sion is that it is more efficient and more certain in its effects, but some physicians prefer the bromide of ammonium or of lithium, and others still prefer a mixture of two bromides. In severe eases it is some- times found that the bromide action is strengthened by the addition of cannabis indica, opium or chloral, although the last two are to be used with caution. In the treatment of epilepsy it is well to begin with small doses and to increase them up to 10 G. per day, or until the de- sired effect is attained, or some complication, such as widespread skin affections, precludes their further use. When little chloride is taken in the food the excretion of bromide is much retarded, and, on the other hand, the addition of chloride to the dietary accelerates the bromide excretion. The restriction of the salt in the food of epileptics under bromide treatment has therefore been suggested with the object of saturating the tissues with smaller doses of bromide than would other- wise be necessary. In practice, however, it is difficult to reduce mate- rially the chlorides of the food, and equally satisfactory results may be obtained, with less hardship to the patient, by slightly increasing the dose of bromide. The acne is very often a troublesome accompaniment of the bromide action, and in fact may prevent the use of this valuable drug in other- wise suitable cases. It may often be prevented by scrupulous clean- liness of the skin and frequently yields to treatment with small doses of arsenic. The bromides are not so effective in other affections of the central nervous system, although some success has attended their use in chorea, in the convulsions of children, and in some forms of hysteria. They have also been used in tetanus and in strychnine poisoning, but are inferior to other remedies such as chloral. Neuralgia is sometimes improved by bromide treatment, especially when it arises from worry, anxiety, or overwork. As soporifics, bromides often fail entirely, or induce such depression and confusion subsequently as to preclude their use. In sleeplessness from anxiety, they are often valuable, however, and it is found that the dose of chloral may be considerably lessened, if it is prescribed along with bromides. In sleeplessness from pain, bromide is of little or no value. Bromides have been used with good results in sea-sickness, in the 506 INORGANIC SALTS, ACIDS AND BASES. sickness of pregnancy, and, it is said, in whooping-cough. Bromide of potash was formerly given internally to lessen the reflex movements of the throat and thus to permit of laryngoscopic manipulations, and it was also applied locally to the throat for this purpose. It has now been superseded by the local use of cocaine. THE BIBLIOGRAPHY of potassium bromide, up to 1877, is given fully by Krosz. Arch. f. exp. Path. u. Pharm., vi., p. 1. See also Albertoni. Ibid., xv., p. 248. Loewald. Kraepelin's Psych olog. Arb., i., p. 489. Ach. Ibid., iii., p. 203. Wiersma. Ztsch. f. Psych, u. Phys. d. Sinnesorgane, xxviii., p. 179. Nencki u. Schoumow-Simanowsly. Arch. f. exp. Path. u. Pharm., xxxiv., p. 313. Heftcr. Ergebnisse der Physiologic, ii., 1, p. 102. Bistroff. Arch. f. Anat. u. Phys., 1868, p. 721. (Ammonium bromide.) Amory. Bromide of Potassium and Bromide of Ammonium, Boston, 1872. Wdr Mitchell American Journ. of Med. Sciences, lx., p. 440. (Lithium bromide.) Heichert. Boston Med. and Surg. Journ., civ., p. 505. (Hydrobromic acid.) Hosenthal. Ztschr. f. phys. Chem., xxii., p. 227. V. IODIDES. Although the iodides have been more largely used in medicine than any of the other salts of the alkalies, their mode of action is still wrapped in obscurity. This is due to the unsatisfactory state of the pathology of the diseases in which they are used, to the fact that the attention of investigators has been drawn to the symptoms of poison- ing rather than to the therapeutic action, and also to the fact that the effects seem to vary very considerably not only in different individuals, but also in the same person at different times. Symptoms. Large quantities of the iodides cause irritation of the stomach from their salt-action, and induce nausea and vomiting, more rarely diarrhoea ; but these symptoms are quite distinct from those known as lodism, which may arise from comparatively small quanti- ties, and which are most commonly seen when the remedy has been administered repeatedly. The commonest symptom of iodism is catarrh of the Respiratory Passages, more especially of the nose, which betrays itself in some swelling and discomfort in the nasal mucous membrane, in a profuse watery secretion, and in sneezing. The catarrh spreads upwards to the conjunctiva, which often becomes swollen and congested, and to the frontal sinuses, where it induces a feeling of dulness or violent headache ; it also progresses downwards to the tonsils, which become swollen and inflamed in some cases. Still lower it occasionally causes some swelling and oedema or small ulcers in the larynx, and has thus caused dyspnoea, which has necessitated tracheotomy, or very rarely has proved fatal. Bronchitis has also been observed in man, with a profuse watery secretion, and in animals oedema of the lungs and pleuritic effusion have been produced by the injection of iodides. Even small quantities injected intravenously increase the mucus se- creted by the bronchi. IODIDES. 507 In the Mouth iodism is often betrayed by swelling and irritation of the throat and tonsils, and by salivation, rarely by swelling of the salivary glands. The stomach is seldom affected, the appetite generally remain- ing good, but in some persons iodides induce nausea and gastric dis- comfort. Skin Eruptions of different forms are also common results of the administration of iodides, but are less liable to occur in the beginning of the treatment than the catarrh of the respiratory passages. These eruptions may simulate almost all known skin diseases, but the most common forms are erythematous patches, or papular eruptions which may pass into pustules or into larger inflamed areas. Eczema, bullse, pemphigus, and purpura arise less frequently from the use of iodides. In some cases, a more or less defined area of oedema has been observed in the face. The Secretion of Urine is generally increased by the administration of iodides, as of other salts of the alkalies, though they seem to have no specific action on the kidneys. In rare cases albuminuria has been observed, and some irritation of the bladder, urethra, and vagina is said to have been induced by iodide treatment, but these statements require confirmation. Not infrequently the Pulse is accelerated, though this is not constant. The Central Nervous System seldom seems to be affected by the treat- ment. In rare cases paralysis, tremors and various disorders of sen- sation, such as localized anaesthesia or neuralgic pains, have been recorded, but it seems open to question whether these were in all cases the direct result of the medication. A slight rise of Temperature has also occurred, often apparently from the skin affections or the catarrh ; in some doubtful cases apparently without any such cause. Loss of Weight has been noted a number of times both in man and animals. This is seen more frequently in thyroid disease (goitre) than elsewhere, and in these cases the goitre is often reduced in size. It is still disputed whether the prolonged use of iodides lessens the size of the testicles and of the mammary glands. In some rare cases of very prolonged iodism, a Cachexia has been observed, with great loss of flesh, weakness, depression, mental con- fusion, restlessness and aberrations of sensation. These did not disap- pear at once when the treatment was discontinued,, as the ordinary symptoms of iodism do. In many instances, small doses of iodide may be given repeatedly without any noticeable disturbance, but in others, the smallest quantity (0.2 G.) induces severe poisoning. Some authorities consider that these small doses are more liable to cause iodism than larger ones, but this may be doubted, as the action of the drug is so capricious, that the statistics of different observers show great discrepancies, even when approximately the same dose has been given. Thus, Haslund, treating patients with at first 3 G. (45 grs.) and then 5 G. (80 grs.) daily, observed iodism in only 12 per cent, of his cases during the first 508 INORGANIC SALTS, ACIDS AND BASES. few days, while others have found iodism induced in 60 per cent, of their cases after a single dose of 3 G. An attempt has been made to explain these discrepancies by supposing that iodism is only produced by impure iodides, but this is not correct, for it has been observed in numerous cases in which the drug was absolutely pure. Among other conditions which favor the onset of symptoms, is a slow excretion of the iodide such as is observed in some forms of renal irritation. Children seem less liable to suffer from the iodides than adults. The dose administered has, of course, some relation to the onset of symp- toms ; thus, very large doses are more likely to induce them than very small ones, but it seems that a tolerance is soon established in some cases, for after iodism has been induced, and the daily dose lessened accordingly, it is sometimes found that it may be gradually increased until a quantity considerably greater than that originally given may be taken with impunity. In other instances, a definite quantity may be given for a long time without inducing symptoms, but these may sud- denly set in without any apparent change in the treatment and without any appreciable cause. Very often it is found that the symptoms dis- appear when the treatment is continued, and recovery invariably sets in when the drug is abandoned. The iodides all induce iodism, the symptoms being apparently unaffected by the basic ion, but the iodide of ammonium is said to be more liable to induce them than the others, owing to the iodine being freed from it more easily. The symptoms are seldom dangerous, but a few cases are recorded in which oedema of the larynx resulted and proved fatal, and in others death was attri- buted to the iodides, but the exact cause was not ascertained. The iodides are not Absorbed from watery solutions applied to the skin, but are rapidly taken up by all the mucous membranes. When given by the mouth they are absorbed unchanged by the stomach and intestine, and appear in the secretions within a few minutes. The greater part of the iodide is Excreted in the urine, in which it ap- pears as salts. Some escapes by the salivary glands, however, and small quantities are excreted by the stomach as hydriodic acid and some- times as free iodine ; iodide has also been found in the tears, per- spiration, milk, sebum, and in the secretion of the nasal mucous membranes. No iodine can be detected in the breath of animals poisoned with iodides. After treatment with iodide of potash, iodine has been detected in the hair, milk, muscles and heart in organic combination. Iodides are much more rapidly excreted than bromides, for 65-80 per cent, of the iodide appears in the urine within 24 hours after its administration, and no iodide reaction is obtained from any of the secretions a week after the treatment has ceased. It has been stated that iodide fails to pass into the serous cavities in inflammatory transu- dates, but this seems to be incorrect, although the starch test often fails here from the presence of proteids. The greater part of the iodide administered therefore passes through the tissues and is excreted in the urine in the form of salts. If iodide of potassium be given, as is generally the case, some inter- IODIDES. 509 change between it and the salts of the tissues takes place and iodide of sodium, chloride of potash and several other salts are formed, and all of these are excreted in the urine. Some of the iodide undergoes decomposition in the body, however, and the free iodine thus formed is believed to be the cause of the symptoms of iodism. This decompo- sition of iodides in the body was at first rather inferred from the sim- ilarity of the symptoms with those induced by iodine preparations, than from the actual demonstration of the presence of iodine in the tissues. The ordinary iodine tests fail in albuminous solutions, because it ap- pears to exist in a loose combination with the proteids, but free iodine has been shown to be excreted into the stomach, and an organic com- pound of iodine exists in the hair and in various internal organs after iodide treatment. The successful treatment of goitre with iodide of potassium is also a strong argument in favor of the presence of free iodine, and the iodothyrin of the thyroid gland has been shown to be increased by potassic iodide. When iodine is thus liberated in the body, it does not circulate as such, but at once combines with the pro- teids. The formation of free iodine from iodides (which is, of course, quite dis- tinct from their dissociation into potassium and iodide ions) has been ex- plained by several theories. The first of these assumed that the iodide was decomposed by the carbonic acid of the blood, forming hydriodic acid, and that this was subsequently oxidized in the blood to free iodine. Binz sup- posed that the decomposition occurred rather in the protoplasm of the tis- sues, and supported his statement by an experiment in which an iodide solu- tion was saturated with carbonic acid and had plant protoplasm added to it, after which it gave the ordinary iodine reaction with starch. The objection has been raised that this experiment succeeds only when dying protoplasm is used, and another theory has been proposed, namely, that the oxidation is carried on, not by the protoplasm itself, but by some unstable substances which are excreted by living matter, and which therefore occur on the mucous membranes, in the saliva and elsewhere. These bodies are in themselves reducing agents, but in the presence of air, as in the respiratory passages, their oxidation is accompanied by the liberation of "active oxygen" which in turn oxidizes the iodides. Another explanation which has been given for the occurrence of free iodine is the action of nitrites, which decompose iodide of potassium in the presence of acids. But Anten found that iodism is not induced more readily in a susceptible subject when the nitrites are augmented in the tissues. It has been stated recently that iodism is very readily elicited in patients whose saliva contains much sulphocyanide, and that the occurrence of this body in the secretions of the respiratory tract is responsible for the manifes- tations of irritation induced by iodides. Binz has found that some microbes are capable of setting iodine free from acid solutions of the iodides. Iodine is supposed to be set free along the mucous membrane of the respiratory passages and in the skin ; and in this way the coryza of the former, and the eruptions on the latter are explained. It must be noted that free iodine has not yet been clearly demonstrated in either of these surfaces, and that the theory has been formulated only to explain the symptoms of iodism. Iodides have been found in the nasal secretion, saliva, and perspiration, but no free iodine. Some of the other symp- 510 INORGANIC SALTS, ACIDS AND ASES. toms of iodism are probably due to action on the thyroid gland; thus the acceleration of the heart observed in some cases, the loss of flesh resulting from their prolonged use in others, and the reduction in the size of goitres may all be explained in this way. (See Thyroid Extract.) The central nervous system and the circulation scarcely seem to be affected by iodides. Very large quantities of potassic iodide injected into a vein are found to weaken and paralyze the heart in animals, but do not seem to be more poisonous than other potassium salts, and depression of the central nervous system may also be elicited in the same way by the potassium action. Barbera states that very large quantities of iodides paralyze the depressor nerve terminations in the medulla oblongata and weaken the pe- ripheral inhibitory mechanism of the heart, while Hunt found the accelera- tor fibres less easily fatigued after iodide. The metabolism of the body seems little affected by iodides in most cases, but a further examination of the excretions of patients who lose weight under the treatment is desirable. The action of the iodides in therapeutics has been ascribed by some authors to their rendering the movement of the leucocytes (diapedesis) more active, but no satisfactory evidence has been adduced in support of this. Solutions of iodide of sodium are found to be more poisonous to muscle, cilia and unicellular organisms exposed to them than are similar solutions of the chloride or bromide, so that the iodide ion appears to be more fatal to protoplasm than the bromide and chloride ion, while it is less poisonous than the fluoride. In the frog stiffness and awkwardness in the movements are elicited by comparatively small doses of iodide of sodium and these symp- toms have been shown to be due to rigor mortis occurring in the muscles. PREPARATIONS. POTASSII IODIDUM (U. S. P., B. P.) (KI), 0.1-1.3 G. (2-20 grs.). Unguentum Potassii lodidi (U. S. P., B. P.). Linimentum Potassii lodidi cum Sapone (B. P.). SODII IODIDUM (U. S. P., B. P.) (Nal), 0.1-1.3 G. (2-20 grs.). Ammonii lodidum (U. S. P.) (NH 4 I), 0.1-1 G. (2-15 grs.). Strontii lodidum (U. S. P.) (SrI 2 ), 0.3-1 G. (5-15 grs.). Syrupus Acidi Hydriodici (U. S. P.), a syrup containing about 1 per cent, by weight of hydriodic acid. 4 c. c. (1 fl. dr.). Acidum Hydriodicum Dilutum (U. S. P.), 10 per cent. 0.5 c.c. (8 mins.). The iodides form colorless crystals when pure, a yellowish tint indicating the presence of free iodine. They are very soluble in water, less so in alco- hol, and are always prescribed in watery solutions, and often along with carbonates of soda or potash, in order to prevent decomposition as far as possible. The iodide of potash is the one most frequently used and is less liable to contain free iodine than the others, but iodide of soda is preferred by some ; the dose often has to be much increased beyond that given above. The iodide of ammonium is said to be more liable to cause skin eruptions and disturbance of the digestion than the others. Some iodide effects may also be obtained by the use of iodide of lead or mercury, but here they are complicated by the action of the metal, and these will be discussed along with the other salts of lead and mercury. The external application of iodides, as in the ointment or liniment of potassic iodide, is not attended by any effect local or general. Therapeutic Uses. - The iodides are used very extensively in the treatment of tertiary syphilis, in which they have proved invaluable. They have also been administered in the earlier stages of the disease, but have proved to be of little service here. In syphilitic bone disease IODIDES. 511 and ulcers, and in the gummata of the brain and other internal organs, however, a remarkable improvement very often occurs after the iodide treatment has been adopted. The iodide of potassium or of sodium is almost invariably used, and is given in as large doses as the patient can bear, often up to 5 G. (75 grs.) daily. In the beginning of the tertiary manifestations, the iodide is often prescribed along with mercury, and this combination is found more efficient than the iodide alone. No explanation of the action of the iodides in syphilis has been given, although it is surmised that they may act as a specific poison (anti- septic) to the unknown cause of the disease. It is suggested by some writers (Binz) that the iodine is set free in the gumma or in its neigh- borhood, but this is pure speculation, unfounded on any basis of fact. In many diseases which are not directly attributable to syphilis, but in which there is a history of syphilis, iodides are of value ; thus, neuralgia and other nervous disturbances are often relieved by them in persons of a syphilitic taint, and in fact, improvement is often ob- served in the most diverse conditions in persons who have formerly suffered from this complaint. Another series of symptoms or of diseases which is often treated with iodides, is rheumatism in its various manifestations. The treat- ment is of little value in acute rheumatism, and in fact, often fails in the chronic disease, but is occasionally attended with improvement, although the exact conditions in which this occurs are still unknown. The iodides have long enjoyed some reputation in the treatment of goitre, but the thyroid extract has proved much superior to them and promises to supplant them entirely, as their effects are due to their action on the thyroid secretion. The same may be said regarding their use in obesity, which was found to be successful in some cases, pre- sumably of thyroid insufficiency. In normal persons and animals it is often found that iodides rather tend to increase than to decrease the weight. Some skin eruptions have been found to be benefited by the iodide treatment even when no suspicion of syphilis could be entertained. (Compare thyroid extract.) The success attending the treatment of goitre with iodides seems to have been the basis of their use in cases of enlarged lymphatic glands, scrofula, and lupus, but here the results are very doubtful, although some authorities allege that the iodide treatment is of value. There is a general consensus of opinion that the old treatment of malignant tumors, such as cancer and sarcoma, with iodides is hopeless. These salts are sometimes credited with promoting the absorption of serous effusions, but here again it seems doubtful if their reputation is merited. The same may be said of their use to aid in the removal of hypertrophy of connective tissue in the body, as in the various forms of sclerosis and cirrhosis, although the iodides are still very widely used in arteriosclerosis. Their effect in removing the syphilitic gumma was evidently the origin of their use here, but while the resolu- tion of gummata under the iodides is beyond question, the evidence of 512 INORGANIC SALTS, ACIDS AND BASES. improvement in arteriosclerosis in patients free from syphilitic taint is not so decided, and in fact the use of iodides in this condition is con- demned by many authorities. Iodide treatment has no eifect on the heart, pulse, or blood-pressure in arteriosclerosis even after prolonged use. Heinz has attempted to find a scientific basis for the treatment of exudates and connective tissue hypertrophy with iodides, and sug- gests that the vessel walls are rendered more permeable and the leuco- cytes more active by these salts, but fails to bring any convincing evi- dence for either hypothesis. At one time aneurism was treated with large doses of iodide, and improvement was undoubtedly observed in some cases, in which there was probably a syphilitic taint ; but there seems no reason to suppose that the iodides have any special action on the vessels apart from their antisyphilitic action. Iodides are often prescribed along with other remedies in expecto- rant mixtures, the object being to render the bronchial mucus more watery and less tenacious, and thus to facilitate its removal. In some cases of asthma they have been found of value, perhaps from the same action. Iodide of potassium is generally prescribed in chronic poisoning from lead or mercury, and is believed to hasten the elimination of these metals, although it has not been shown that it is of more value here than other salts such as the chlorides and bromides. The belief in the efficacy of the iodides in mercury poisoning has suggested that they act in tertiary syphilis only by aiding in the elimination of the mer- cury stored in the tissues from the treatment of the earlier stages, but this is incorrect, for the iodides are of value in cases of tertiary syphi- lis in which mercury has not been previously used. Finally, iodide of potassium is sometimes added to other drugs in cases of malingering, or in which it is suspected that the patient is not taking the remedy as directed. If the iodide is swallowed it can be detected in the urine by the addition of a few drops of chlorine water and of starch solution, which assumes the well-known blue color. Iodides have to be used with care in cases of pulmonary phthisis, in which they often increase the cough and expectoration, and in some cases, it is alleged, cause haemoptysis. Children have sometimes been found to suffer with iodism from being nursed by a person under iodide treatment. Iodism very often proves a disagreeable accompaniment of the treatment, and is sometimes so severe as to preclude the use of the salts, so that many attempts have been made to discover some expedi- ent by which these symptoms may be avoided. Most of these were based on the view that iodism arises from the action of nitrites in an acid medium, but doubt may be entertained as to the validity of this hypothesis, and there can be little question of the inefficiency of sul- fanilic acid and alkali carbonate treatment in cases of iodism. There has been a tendency recently to ascribe the symptoms to the tissues being flooded with large quantities of iodide, which are necessary on IODIDES. 513 account of the rapid excretion, and more slowly absorbed preparations have been suggested, such as the combination with fats (lodipin, p. 516) ; the absorption of iodide of potassium may be retarded somewhat and its action prolonged by prescribing it in mucilaginous fluids. The cutaneous eruptions are said to be less liable to occur when the skin is kept scrupulously clean by frequent bathing. BIBLIOGRAPHY. Blum. Munch, med. Woch., 1898, pp. 231 and 267. Binz. Virchow's Arch., IxiL, p. 124. Arch. f. exp. Path, u, Pharm.. viii., p. 320 ; xiii., p. 139 ; xxxiv., p. 185. Boehm u. Berg. Arch. f. exp. Path. u. Pharm., v., p. 329. Hogyes. Ibid., x., p. 250. Adamkiewicz. Char. Annal., iii., p. 381. Singer. Ztschr. f. klin. Med., Iii., p. 521. Lesser. Deutsch. med. Woch., 1903, No. 46. Ehrlich. Char. Annal., x., p. 129. Groenouw. Therap. Monatsh., 1890, p. 105. Rohmannu. Malachowski. Therap. Monats., 1889, p. 301. Kulz. Zeitschr. f. Biologic, N. F., v., p. 460. Nencki u. Schoumow-Simanowski. Arch. f. exp. Path. u. Pharm., xxxiv., p. 313. Ehlers. Monatsh. f. pract. Dermatol., 1889, i., p. 428. Prevost u. Binet. Therap. Monatsh., 1890, p. 640. Howald. Zts. f. physiolog. Chem., xxiii., p. 209. Annuschat. Arch. f. exp. Path. u. Pharm., x., p. 261. Anten. Arch. f. exp. Path u. Pharm., xlviii., p 331. Stockman and Charteris. Journ. of Physiol., xxvi., p. 277 ; Brit. Med. Journ., Nov. 23, 1901. Heinz. Virchow's Arch., civ., p. 44. Gumprecht. Verhandl. d. Congress, f. inn. Med., xix., p. 260. VI. IODINE. Iodine possesses a local irritant action similar to, though less intense than that of chlorine and bromine. It is much less volatile, and there- fore comes into contact with the tissues more slowly than these, but the chemical change is analogous, and iodides and proteid compounds result. 1 Action. When applied to the Skin, it dyes it a yellow-brown or dark brown color, and acts as an irritant, producing a sensation of heat and itching. In very concentrated solution or in the solid form, it may cause blistering or even corrosion, but it acts much more slowly than most other irritants, and at the same time the irritation is more prolonged. It penetrates into the deeper layers of the skin, and small quantities are absorbed. The Mucous Membranes are more strongly affected by contact with it ; thus when its vapor is inhaled for some time, smarting, swelling and increased secretion is caused in the nasal mucous membrane, conjunctiva, throat and lower respiratory passages, resembling exactly the symptoms known as iodism. In the stomach small quantities may 1 It therefore differs entirely from the iodides and the other salts, as far as its local action is concerned, but there are so many points of connection between the halogen and the salts that it has been found convenient to insert it here. The same remark holds good for the next series (lodoform). 33 514 INORGANIC SALTS, ACIDS AND BASES. cause slight irritation and improved appetite, but as a general rule nausea, discomfort and vomiting follow its administration in any save the most minute doses, and occasionally diarrhrea has been observed after it from irritation of the bowel. In cases of poisoning, the irri- tation of the alimentary canal may prove fatal by inducing collapse and failure of the heart and respiration, and iodine may be recognized in the vomited matter and in the stools. Solutions of iodine Injected Subcutaneously or into tumors or cysts, a common method of treatment formerly, cause intense pain and irri- tation which may induce collapse and which have been followed in some instances by suppuration and gangrene. Iodine is Absorbed in the form of iodides, and perhaps in a combi- nation with proteids. The ordinary iodalbuminate obtained by adding iodine to albumin, is a very loose compound, and is easily decomposed by dialysis, or by heating it to the coagulation point of the albumin, when the iodine is obtained free or in combination with alkalies. Sev- eral stronger and more definite compounds have been formed recently, and it is not impossible that the iodalbuminate formed in the process of absorption is of a similar nature. In combination with albumin, iodine fails to give the starch reaction. Its Fate in the Body is pre- cisely similar to that of the iodides it is excreted in the form of iodides, chiefly by the kidneys, to a less extent in the saliva, perspira- tion, milk, and secretions of the respiratory passages. It also occurs in the stomach, into which it appears to be excreted as hydriodic acid ; free iodine has been detected here in both man and animals, and is probably formed by the decomposition of the acid. In the normal organism iodine is contained in considerable quantity in the thyroid gland in the form of an organic compound, iodothyrin, and in many cases the administration of iodine leads to an increase in the for- mation of this substance, perhaps by actually stimulating the secretory cells of the thyroid, but more probably by affording them a larger amount of a necessary constituent of their secretion than is contained in ordinary food. Small quantities of iodine may be given internally to many persons without eliciting any symptoms except those which are clearly due to the local action. Repeated doses, however, sometimes cause symp- toms resembling those observed after iodides (lodism), although these have been much less often induced by iodine, which is comparatively seldom administered internally. Skin affections seem to be extremely rare, but that a similar action on the skin may be induced by iodine and iodides, is shown by the application of iodine to the skin being often followed by eruptions, which are not confined to the point of application but spread over the skin and assume the form of diffuse erysipelatoid rashes, papules, or erythemata. Fever is said to occur occasionally, especially in goitrous patients, and a loss of flesh has been observed with shrinking in size of the thyroid gland and, it is said, of the mammae and testicles. The puke is often accelerated to a very considerable extent, and in cases of goitre treated for some time by the IODINE. 515 internal and local administration of iodine, a curious nervous condition was often observed formerly. The patients became restless, anxious and irritable, and suffered from sleeplessness and often from tremor, which sometimes simulated chorea. All of these symptoms except the skin eruptions and the atrophy of the mamma and testis, the occurrence of which under iodine requires confirmation, are induced by large quanti- ties of thyroid extract also, and would seem to be due to the excessive production of iodothyrin. Irritation of the respiratory tract is seen less often after iodine than after the iodides, but oedema of the larynx has been observed, and in rare cases cough and the expectoration of a watery secretion tinged with blood. Anuria and albuminuria have occurred in a few instances. The symptoms induced by iodine after absorption thus resemble in general features those following the use of the iodides, but while the latter tend to cause irritation of the skin and respiratory tract, pre- sumably through liberating iodine here, the chief effects of iodine after absorption are due to its action on the thyroid gland, the effects on the skin and mucous membranes being less prominent. The effects of iodine on the Metabolism are still a matter of dispute, some authors finding no alteration, while others state that the excretion of urea is increased. They probably differ in different individuals according to the condition of the thyroid gland. Injected into the veins of animals, iodine causes oedema of the lungs, which v. Zeissl considers to be due in part to changes in the left ven- tricle, in part to contraction of the pulmonary arterioles. The muscles of the frog are thrown into a state of rigor by iodine in the same way as by the iodides. Some Cases of Poisoning from the injection of large quantities of iodine into cysts have been recorded. In Rose's well-known case, the chief symptoms were thirst, constant vomiting, the vomited matter containing iodine, cyanosis and coldness of the skin, a small, weak pulse, anuria and skin eruptions after a few days ; and death occurred on the tenth day. In such cases of poisoning in man the mucous membrane of the stomach and intestine has been found swollen and loosened, and in animals fatty degeneration of the liver, heart and kidney has been described. Iodine is said to dissolve the red blood corpuscles when it is brought in contact with them outside the body, and to form a combination with hemoglobin. PREPARATIONS. lodum (U. S. P., B. P.), iodine, a heavy, friable, bluish-black mass, with a characteristic odor and acrid taste, insoluble in water, soluble in alcohol and in solutions of the iodides of the alkalies. Iodine itself is not used in therapeutics. The solutions are of a brown color. Tinctura lodi (U. S. P.), 7 per cent., 0.1-0.4 c.c. (2-8 mins.). Tinctura lodi (B. P.), 2 per cent., 2-5 mins. Liquor lodi Compositus (U. S. P.), Lugol's Solution, contains 5 per cent, dissolved in 10 per cent, potassium iodide solution. 0.2-0.8 c.c. (3-12 mins.). 516 INORGANIC SALTS, ACIDS AND BASES. Unguentum lodi (U. S. P., B. P.), 4 per cent Liquor- lodi Fortis (B. P.), Iodine Liniment, about 14 per cent. Sulphuris lodidum (U. S. P., B. P.) is a mixture of iodine and sulphur, part of which may be in chemical combination. It resembles iodine in its action on the skin. Unguentum Sulphuris lodidi (K P.). The compound solution of iodine is the preparation best fitted for internal use, although the tincture is also employed. Both should be given after meals and as far as possible diluted with demulcent preparations, in order to avoid irritation of the stomach. For injection into cysts or tumors the compound liquid is also the best preparation, as it is less irritant than the tincture. The tincture, ointment, the strong solution (B. P.) and the sulphur iodide preparation may be used for external application. Therapeutic Uses. Iodine has been used internally in a variety of chronic conditions such as syphilis and goitre, and in tubercular dis- ease of the glands, bones and other organs, but it has been almost entirely superseded by the iodides, and in goitre by the thyroid prepara- tions. It was formerly applied in goitre by injection into the enlarged lobes of the gland, as well as being administered internally, and cer- tainly proved beneficial in many cases, though these are better treated now by the extracts of the gland. The internal use of iodine has undergone a revival quite recently, but in- stead of the older solutions, new preparations have been introduced such as the combinations with proteids (Eigon, lodolen) or with fats (lodipiri), and the organic compounds of the iodoform series. lodipin is decomposed by the pancreatic juice and iodides appear in the urine soon after this takes place. It has been used to indicate the activity of the gastric movements, as when these are abnormally slow the reaction in the urine appears later than in normal cases. Iodine has been applied locally by painting on the skin in a variety of chronic inflammatory processes, such as tubercular glands, pleuritic effusion, and tubercular or rheumatic joint disease. Its action here consists simply of a mild lasting irritation of the skin, which induces some congestion in the subcutaneous tissues and may thus aid in the absorption of exudates in them and may also influence the deeper lying tissues and organs in the same way as other irritants (see page 78). There is, however, nothing specific in its action, and it differs from the other skin irritants only in being milder in action and more enduring in its effects. It seems unlikely that the small quantity absorbed can have any appreciable action. Some benefit often follows from this use of iodine in chronic inflammations, but there is no question that it is very often applied where more active surgical measures are really required. Iodine has been very frequently injected into cysts in order to in- duce inflammation and adhesion of their walls, and thus to obliterate the cavity. Formerly ovarian cysts were very generally treated in this way, but a number of cases of poisoning arising from this treat- ment, and the progress of abdominal surgery have led to its being abandoned. Hydrocele is still very frequently treated with iodine in- IODOFORM. 517 jection, and some cysts of the membranes of the spinal cord and brain are injected with it. It has been stated in this connection that these membranes react much less violently to iodine than the peritoneum and the lining membranes of the joints. Iodine has also been injected in dilute solution into the pleuritic cavity after the evacuation of empyema. BIBLIOGRAPHY. See Iodides, Thyroid Extract. Liebrecht. Centralbl. f. Physiol., 1897, p. 835. Hofmeister. Ztschr. f. phys. Chem., xxiv., p. 159. Winternitz. Ibid., xxiv., p. 425. Levene. Amer. Journ. of Phys., ii., p. 15. VII. IODOFORM. A number of iodine compounds have been introduced into thera- peutics as applications to wounded surfaces. The most widely known of these is lodoform (CHI 3 ), which corresponds in its chemical struc- ture to chloroform, and forms a yellow, crystalline, insoluble powder with an intensely disagreeable odor. It has been used very exten- sively in surgery, and has given rise to poisoning in a number of cases. Symptoms. The symptoms of iodoform intoxication in man gener- ally set in with anxiety, general depression and discomfort. The pa- tient becomes sleepless and restless, complains of giddiness and head- ache and often of the taste and odor of iodoform in the mouth and nose. The pulse is generally greatly accelerated, and a rise of tem- perature is said to have occurred in some cases in which no septic poisoning could be found to account for it. The depression deepens into true melancholia accompanied by hallucinations, the patient often suffering from the illusion of persecution, which may induce him to attempt suicide. As a general rule this melancholia is followed by attacks of violent delirium and mania, lasting for hours or days, and in fatal cases, by collapse and death. In other cases the condition has passed into permanent insanity and dementia. A rarer result of the absorption of iodoform is deep sleep passing into stupor and collapse without any symptoms of cerebral excitement. In milder cases of poisoning the patient suffers only from the un- pleasant taste and odor, from headache and not infrequently from nausea and vomiting. In the dog and cat iodoform generally causes deep sleep and stupor, with lessened excitability of the spinal cord and of the motor areas of the brain. In the frog it paralyzes the central nervous system and the heart without eliciting any symptoms of excitement. No narcosis is observed in the rabbit even after fatal doses. The symptoms most characteristic of iodoform poisoning those of delirium and mania are evidently due to cerebral disturbance, but nothing is known as to the nature of the changes in the brain. No other poison elicits these symptoms in the same intensity and of equal duration, and no similar effects have been met with in animals. 518 INORGANIC SALTS, ACIDS AND BASES. Acceleration of the heart has been noted in many cases of poisoning. After prolonged administration albuminuria is often observed in ani- mals, and the thyroid secretion has been found to be increased to a very considerable extent by iodoform, as by other bodies which free iodine in the tissues. After fatal iodoform poisoning in man and animals, the liver, kidney, heart and muscles are generally found to have undergone fatty degen- eration. In addition, irritation of the gastric and intestinal mucous membrane has been observed, and the epithelial cells are often degen- erated. Ecchymoses occur beneath the endocardium, in the kidney and elsewhere, and congestion of the meninges is described. Absorption and Excretion. Iodoform is readily decomposed in the presence of alkaline fluids and in proteid solutions, and some decom- position undoubtedly takes place in wounds ; the iodine liberated combines with the alkalies of the fluids to form iodides, for these have been shown to be present, and iodalbuminates are presumably formed in the same way as by free iodine. Some of the iodoform, however, is absorbed unchanged, for the nervous symptoms are not produced by iodine or iodides. After iodoform absorption, iodine has been shown to be present in the saliva, perspiration and bronchial secretion, as after the ingestion of iodine or iodides ; but it is chiefly excreted in the urine in the form of iodides. The tissues apparently retain it very tenaciously, for iodides have been found in the urine for more than a month after the administration of iodoform. In considering the symptoms of iodoform intoxication, it must be recognized, therefore, that a very complex condition is present. Some iodoform circulates in the blood apparently unchanged and gives rise to the cerebral symptoms. Other symptoms are due to the presence of iodine and iodides, perhaps the former chiefly, in the blood and tis- sues, for Rummo observed in dogs the excessive secretion from the eyes, nose and bronchi, which is characteristic of iodism. Lastly, the acceleration of the heart and some other symptoms may be due to abnormal activity of the thyroid secretory cells. Poisoning with iodoform is much more liable to occur in adults than in children. Serious symptoms, especially mental symptoms, are often developed only after somewhat prolonged administration, but in renal disease the iodoform products are excreted^more slowly than usual, and are liable to accumulate in the tissues, so that it is to be used with caution. Iodoform has no marked Local Action on the skin or mucous mem- branes. When applied to wounded surfaces it sometimes causes some irritation in the neighborhood and even exanthemata, but these are rare, and appear to occur only in persons predisposed to cutaneous disease. It seems to have some ansesthetic action, when applied in large quantity to wounded surfaces. Iodoform was at first applied to wounds in the belief that its Antiseptic properties were equal to or even exceeded those of carbolic acid. It has been shown, however, that it possesses little or no influence on the cultures of most of the pathogenic mi- IODOFORM. 519 crobes, for the spores often develop as rapidly after having been sub- jected to iodoform as in the control cultures. It has therefore been suggested that while iodoform in itself possesses no antiseptic virtues, the iodine formed from it in the wound ma} 7 retard the growth of sep- tic germs. And in regard to this point bacteriologists are not agreed, for while several investigations tend to show that microbes drawn from wounds under iodoform treatment are not retarded or weakened in their development, other experiments indicate that the virulence of some germs is reduced. Some of the advocates of the iodoform treatment therefore ascribe its results to this slight antiseptic action of the iodine, while others suppose that it diminishes the secretion of the wounded surface and thus aifords a less suitable medium for the growth of the germs ; in this relation it may be mentioned that Binz found the emi- gration of the leucocytes from the blood vessels hindered by the local application of iodoform. Finally iodoform may retard the growth of microbes to some extent by forming a crust over the wounded surface, and mechanically preventing them from penetrating to it. The intensely disagreeable odor of iodoform and the considerable number of cases of poisoning noted under its use have led to the intro- duction of numerous substitutes in the last ten years. Some of these have been shown to be practically worthless and have been discarded, while the greater number are apparently used more or less widely, but accurate data as to their value cannot be obtained. None of them seem to be very poisonous, and in most of them the iodine of the molecule is not liberated in the wound or tissues. It is of course impossible to state how far they are capable of replacing iodoform, as long as their exact action in wounds is unknown. The first of these substitutes was iodol or tetraiodpyrrol (C 4 I 4 NH), which has no odor or taste, is insoluble in water, but is absorbed from mucous sur- faces and from wounds. It is decomposed in the tissues, and leads to the excretion of iodides in the urine, and in very large doses gives rise to symp- toms in animals resembling those produced by iodoform. The iodine of iodol is apparently less easily split off the molecule than that of iodoform, and it seems on the whole less liable to produce poisoning, but has been less used of late years than some of its rivals. Among the best known of these are aristol or dithymol-diiodide (C 6 H 2 CH 3 C 3 H 7 OI) 2 , and the sozoiodolates of potassium, sodium, mercury and zinc. Sozoiodolic acid is phenol-sulphonic acid in which two atoms of hydrogen have been substituted by two atoms of iodine (C 6 H 2 I 2 HOSO 2 OH). Iodine compounds of phenol-phthalein are known by the trade names of nosophen, antinosine and eudoxine. Triiodocresol is known as losophan, while europhen is a more complex combination of cresol and iodine ; loretin and vioform are derivatives of quinoline containing iodine. (See also under Bismuth and Alum.) These later u substitutes " for iodoform differ entirely from it and from iodol in the fact that iodine is not liberated by the tissues ; that they pass through the body unchanged, as far as the iodine is concerned, and that they are said to be entirely devoid of poisonous effects, and in fact of any action, save as local antiseptics. Their value as antiseptics can only be determined by further trial. They are almost all phenol derivatives, and any virtues they possess may prove to be due to this fact mainly, and not to their containing iodine. 520 INORGANIC SALTS, ACIDS AND BASES. PREPARATIONS. lodoformum (U. S. P., B. P.), iodoform (CHI 3 ), forms small, lemon-colored crystals, possessing a very penetrating, persistent and disagreeable odor and taste, practically insoluble in water, soluble in alcohol, ether, fixed oils, glycerin, etc. 0.03-0.2 G. Q-3 grs.), in pills or capsules. Suppositoria lodoformi (B. P.), each containing 3 grs. of iodoform. UNGUENTUM IODOFORMI (U. S. P., B. P.), contains 10 per cent, iodoform. lodolum (U. S. P.), C 4 I 4 'NH, a light grayish-brown crystalline powder, taste- less, odorless, insoluble in water. Dose, 0.25 G. (4 grs.). Thijmolis lodidum (U. S. P.), Aristol ((C 6 H 2 - CH 3 - C 3 H 7 - OI) 2 ) a yellowish- brown powder resembling iodol in its properties. The Sozoiodolate of potassium is slightly soluble in water, the sodium and zinc salts more soluble. Mercury forms an insoluble salt which may be dissolved by the addition of sodium chloride. Therapeutic Uses. Iodoform has been used to a very limited extent internally in the treatment of syphilis, and as an intestinal disinfectant. It is chiefly employed in surgical treatment as an application to wounds, skin diseases and burns. In granulating surfaces with a profuse secre- tion, and in slowly healing abscess cavities, it seems to be especially valuable. It may be applied as a dusting powder, as an ointment, or in gauze or bandages saturated with it. It has been shown that it has very weak antiseptic properties, and many surgeons take the precaution of disinfecting the powder before applying it, and use it for its effect on the tissues of the wound and not for its effects on the germs. Applied in ordinary quantity to small surfaces it seems to be a perfectly safe remedy, cases of poisoning occurring only when large cavities are plugged with it, or when it is applied to very large absorbent surfaces. Many attempts have been made to disguise its disagreeable odor, but have been attended with only moderate success. Among the best of the many perfumes suggested for this purpose is cumarin, which is contained in large quantity in the Tonka bean. Iodoform has been credited with some specific action in tubercular disease, but has proved almost inert towards the bacillus. The favor- able results in the local treatment of tubercular abscesses, laryngeal ulcers and similar conditions may with greater probability be attributed to its action on the granulation tissue. In syphilitic ulcers and chan- cres, iodoform has been used very largely and with good effects. Iodol may be used as a substitute for iodoform, and is applied in the same way. The sozoiodolates are used as powders or ointments, or in the case of the sodium, zinc, and mercury salts, in solution. The last is poisonous, and is comparable to corrosive sublimate in its effects. BIBLIOGRAPHY. Rummo. Arch, de Phys., norm, et path., 1883, ii., p. 145. Binz. Arch. f. exp. Path. u. Pharm., viii., p. G09 ; xiii., p. 113. Virchow's Arch., Ixxxix., p. 389. Behring. Deutsch. med. Woch., 1882, p. 278. Zeller. Arch. f. klin. Chirurg., xxviii., p. 590. Zts. f. physiol. Chemie, viii., p. 70. Harnack. Berl. klin. Woch., 1883, p. 723, and 1885, p. 98. Falkson. Arch. f. klin. Chirurg., xxviii., p. 112. Neisser. Virchow's Arch., ex., p. 381. FLUORIDES. 521 Baumgarten. Berl. klin. Woch., 1887, p. 354. Marcus. Berl. klin. Woch., 1886, p. 342. (lodol.) Sattler. Fortschr. d. Med., 1887, p. 362. (lodol.) Lrnnry. Arch. f. klin. Chirurg., liii., p. 787. Meyer. Ibid., lv., p. 676. Schmidt. Arch, internat. de Pharmacodyn. , viii., pp. Ill, 187; ix., p. 107. Altenburg. Ibid., viii., p. 125. VIII. FLUORIDES. The fluorides present many points of difference from the other halogen salts in their chemical reactions and also in their effects in the organism. The fluoride of sodium, which alone has been examined, possesses a power- fully irritant local action, which is seen most clearly when it is applied to the mucous membranes of the eye or of the alimentary tract. In the for- mer it causes congestion and inflammation of the conjunctiva and opacity of the cornea, when it is applied in a two per cent, solution for some time. Small quantities induce irritation of the stomach, nausea and vomiting, and the prolonged administration leads to irritation of the intestines and diar- rhoea ; solutions of the fluorides are absorbed with great difficulty by the in- testinal epithelium. When injected subcutaneously fluorides often induce inflammation and suppuration with necrosis. In frogs small doses induce prolonged fibrillary contractions of the mus- cles throughout the body, which are due to a stimulation of the terminations of the motor nerves. Larger doses paralyze the central nervous system and eventually the motor terminations, and even the nerve fibres. The muscles lose their irritability and pass into very marked rigor, and the heart muscle is also paralyzed by large quantities. In mammals the first symptoms are increased secretion of saliva and tears, acceleration and deepening of the respiration, followed by a condition of weakness and somnolence. Strong fibrillary tremor of the muscles then sets in with occasional stronger twitches, which eventually pass into attacks of general convulsions. In the intervals between the convulsions the animal lies in a state of profound coma. The respiration is finally arrested during an attack of convulsions, the heart continuing to beat for some time longer. Tappeiner found a very marked fall of blood-pressure produced by sodium fluoride, aud attributed it to depression of the vaso-motor centre. It may in part account for the stupor, but this indirect action is in all probability strengthened by a direct depression of the higher nervous centres. The convulsions are central in origin, while the cause of the fibrillary contrac- tions in mammals is unknown. The respiratory centre seems to be first stimulated and then paralyzed. Muscles, nerves and other excised tissues die much sooner in solutions of sodium fluoride than in corresponding ones of the chloride, iodide or bromide, so that the fluoride ion must be assigned a position quite distinct from the other halogen ions in the scale of toxicity. The fluorides absorbed from the alimentary canal are excreted by the urine, but this takes place very slowly, and much of the fluoride is stored up in the body, some in the liver and skin, but most in the bones in the form of calcium fluoride. Crystals of this very insoluble salt are found in masses in the Haversian canals, and increase the hardness and brittleness of the bones. The prolonged administration of fluorides to animals has been found to cause weakness, loss of flesh, and irritation and ulceration of the gums. The fluoride of sodium has considerable antiseptic power, putrefaction be- ing delayed by the addition of one part to 500 of fluid, and one in 200 ar- resting completely the growth of bacteria. It has been used to a very limited extent as a surgical antiseptic. Hydrofluoric acid is an exceedingly powerful caustic, destroying the mucous membranes wherever it comes in contact with them. It has been 522 INORGANIC SALTS, ACIDS AND BASES. observed that workers in certain departments of glass factories, in which the atmosphere contains a small amount of this acid, are very seldom attacked by tuberculosis, and an attempt has been made to treat pulmonary phthisis by the inhalation of very dilute vapors. The results have not been success- ful, although there is no question that hydrofluoric acid is a powerful ger- micide. Sodium fluorosilicate (SiFlNa 2 ) has also been used as an antiseptic in so- lution. It has been found to cause nausea, eructation and slowness of the pulse when swallowed. BIBLIOGRAPHY. Tappeiner. Arch. f. exp. Path. u. Pharm., xxv., p. 203; xxvii., p. 108. Schuk. Ibid., xxv., p. 326. Hewelke. Deutsch. med. Woch., 1890, p. 477. Langgaard. Therap. Monatsh., 1888, p. 178. Gottbrecht. Ibid., 1889, p. 411. Brandl u. Tappeiner. Ztschr. f. Biologie, x., p. 518. Bokenham. Brit. Med. Journ., 1890, p. 355. Miiller. Inaug. Diss., Greifswald, 1889. Siegfried. Arch, internat. de Pharmacodyn., ix., p. 225. IX. CHLORATES. The chlorate of potassium, introduced into therapeutics on the erro- neous theory that it would supply oxygen to the tissues, has been used very extensively for its effects in certain diseases of the mouth. It was supposed to be entirely devoid of poisonous properties, but was shown by Jacobi to give rise to very grave and even fatal symptoms in some instances. In such cases the symptoms are due partly to the salt-action, but chiefly to the specific effects of the chlorate ion. The chlorate of sodium induces these chlorate symptoms, and the chlorate of ammonium is said to be the most poisonous of the three. It would seem that the conditions which determine their appearance are not universally present, for very often large quantities have been taken with impunity, while in other individuals much smaller quanti- ties have induced grave poisoning. Symptoms. The chlorates have a cool, saline taste, which persists for a long time owing to their being excreted in part in the saliva. Concentrated solutions may cause nausea and vomiting from their local salt-action in the stomach, and their absorption is often followed by considerable diuresis from a similar action in the kidney. In the great majority of cases no further effects are observed. In some individuals, however, symptoms arise from the chlorate action quite apart from those mentioned above, which may be induced by chloride of sodium or, in fact, by any other diffusible salt. (See Salt-action, page 485.) These chlorate symptoms may be divided into those of acute and of subacute poisoning, the first arising generally from the administration of a single large dose, the second from smaller quantities taken repeatedly. In Acute Chlorate Poisoning the first symptom is often prolonged and violent vomiting, with pain in the stomach region ; diarrhoea and a dark eyanotic color of the skin and mucous membranes follow, the respiration is at first dyspnoeic and then weak, the pulse quick and feeble, sometimes irregular. The patient CHLORATES. 523 complains of headache, giddiness and muscular weakness, is restless, and eventually becomes comatose before death. In Subacute Poisoning, vomiting and diarrhoea are also observed, and the vomited matter often contains large quantities of bile, less often blood. There may be complete anuria for some time, or the urine is scanty and at first dark colored, then deep reddish-brown ; it contains haemoglobin, methaemoglobin, and haematin in solution. On standing, it deposits casts of brown amorphous particles, which arise from the destruction of the red cells of the blood, and chlorates are contained in it in considerable quantity. The methaenioglobin may disappear from the urine after one or two days, but the casts re- main longer. The skin is often icteric in color, and in some cases erythematous eruptions have been observed. Headache, muscular weak- ness and abdominal pain are complained of, and uraemic symptoms may arise delirium and convulsions, or confusion and coma. Death has followed from these last as late as a week after the first symptoms of poisoning were observed, but in several cases complete recovery has followed even the gravest symptoms. Action. The cause of the symptoms in acute and subacute chlorate poisoning is, apart from the salt-action, a specific effect which the chlorates have on the Red Blood Cells and particularly on the Haemoglo- bin. This is seen especially well when blood is added to a chlorate solution outside the body, for in the course of a short time the blood assumes a dark chocolate brown color, and spectroscopic examination reveals the absorption bands of methaemoglobin and often of haematin. After a time the red blood cells tend to break up, and the methaemoglo- bin is freed in the serum. If large quantities of chlorate be added, the blood becomes quite black in color, and assumes a gelatinous con- sistency. This action of chlorates on the blood arises from their oxi- dizing properties, for other oxidizing agents have the same effects ; the exposure of haemoglobin to such bodies leads to the formation of methaemoglobin, while red blood cells are destroyed and the haemo- globin is liberated in the plasma. But while the formation of methae- moglobin and the haemolysis are both referable to oxidation, the two processes seem to proceed independently of each other, for some oxi- dizing agents induce marked haemolysis with little methaemoglobin, while in others the latter feature is the predominating one. When this transformation of the haemoglobin takes place in ves- sels, the blood is unable to supply the tissues with oxygen, because in methaemoglobin the oxygen is attached much more firmly than in oxy- haemoglobin, and the tissues are incapable of availing themselves of it. If much of the haemoglobin is thus rendered useless, asphyxia results, and this is unquestionably the chief cause of the symptoms and of the fatal issue in the most acute form of intoxication. If a smaller amount of methaemoglobin is formed, it disappears gradually, either by being slowly reformed to haemoglobin, or by the corpuscles containing it being withdrawn from the circulation and broken up. When a con- siderable amount of haemoglobin is transformed, but sufficient remains 524 INORGANIC SALTS, ACIDS AND BASES. to continue the respiration of the tissues, the subacute form of poison- ing results. The blood cells break up and the haemoglobin, methaamo- globin and the debris of the corpuscles thus freed in the plasma are in part excreted by the urine, in part deposited in the spleen, liver, and bone marrow. As in other conditions of excessive destruction of the red blood cells, the bile pigment is increased in amount, and its absorption from the bile capillaries induces jaundice. The excretion of the products of the destruction of the red blood corpuscles in the urine leads to the renal tubules becoming stopped up with brown granular masses, which are in part forced downwards and appear in the urine as casts, but which may lead to an almost complete suppres- sion of urine and to symptoms of ursemic poisoning. In those cases in which death follows several days after the first symptoms, it seems due not to the direct action of the poison, but to the renal changes. Often no actual nephritis is present, but in some cases the epithelial cells seem to be inflamed, probably as a secondary result of the plugging of the tubules. The deposition of the debris in the liver and spleen often causes enlargement of these organs. In these subacute cases of poisoning, then, death is not due directly to the methsemoglobin for- mation, but to the breaking down of the red cells. The post-mortem appearances in chlorate poisoning vary with the form. In acute poisoning the characteristic color of the blood, and the methsemoglobin absorption band in the spectrum are often the only distinct appearances. In less acute cases, the debris of the red cor- puscles is found in the liver, spleen, bone-marrow and renal tubules, while no methsemoglobin may be detected. Some of the red blood corpuscles are found misshapen, however, others are colorless (shadows), and in some the pigment is formed in masses, instead of being gener- ally diffused. Some swelling and ecchymoses of the gastric and in- testinal mucous membrane have been observed. It has been recently stated that some of the symptoms of chlorate poisoning are due to infarcts formed in the smaller vessels from the agglutination of the remains of the red-blood cells, and Silbermann has even failed to inject some parts of the body owing to this plugging of the arteries. This statement has been denied, however, by Mar- chand and Falkenberg, who could find no evidence of such infarction. The haemoglobin of most animals seems equally easily transformed to methsemoglobin by chlorates when it is dissolved in water, but the blood corpuscles of the rabbit and guinea-pig resist their action much more than do those of the dog and of man. Rabbits therefore very rarely show any symptoms of true chlorate action, and die of the potassium or of the salt-action, while dogs and cats exhibit symptoms very like those seen in man. The cause of this immunity of the rabbit's corpuscles is unknown, but may perhaps be explained by their being impermeable by the chlorate salts. It has been found that when the rabbit's blood is concentrated, or when bile is present in quantity in it, the chlorate action may be elicited much more readily than in normal animals. CHLORATES. 525 The nervous symptoms in chlorate poisoning are manifestly due to the blood changes and the uraemia for the most part, though there is reason to believe that under some conditions the brain is also directly affected. The heart is said to be first slowed and then accelerated by the intravenous injection of sodium chlorate. The vomiting does not seem to be due to local action only, for it is seen in animals in which the salt is injected subcutaneously. Very little chlorate is reduced in the blood and tissues, for 90-96 per cent, of the amount administered has been recovered from the urine. Small quantities appear also in the saliva and in other secre- tions, such as the perspiration, milk, tears, and nasal mucus, and some has been found to pass from the mother to the foetus in utero. The chlorates are hardly more antiseptic than other indifferent salts. The Bromates and lodates have been much more seldom the subject of in- vestigation than the chlorates, and are not used in therapeutics. The iodates are more poisonous than the bromates and these again than the chlorates ; the iodates destroy the red cells more rapidly but form less methaBinoglobin than the chlo- rates in test-tube experiments. lodates induce fatty degeneration of the liver, and congestion and extravasation in the alimentary tract. It is not unlikely that some iodide is formed from them in the body. The action of the Perchlorates has been examined by Kerry and Host. In the frog the perchlorate of sodium (NaClOJ induces fibrillary twitching and clonic contractions of the muscles ; the contraction of the muscle is pro- longed in the same way as by veratrine, and rigor eventually follows as in caffeine poisoning. The reflex excitability is increased, and the heart is slow and irregular. The effects of the perchlorate on mammals differ consider- ably in different species ; in the rat, mouse and guinea-pig the reflex excita- bility is enormously increased and tetanic convulsions may arise from this action ; in the cat a certain stiffness, muscular paresis and tremor can be made out after the injection of large quantities of perchlorate, but these animals as well as the rabbit and dog are not killed by even very large quantities. PREPARATIONS. POTASSII CHLORAS (U. S. P., B. P.) (KC1O 3 ), 0.3-1 G. (5-15 grs.). TROCHISCI POTASSII CHLORATIS (U. S. P.) contain 0.3 G. (5 grs.) chlorate of potassium in each lozenge. TROCHISCUS POTASSII CHLORATIS (B. P.) contains 3 grs. in each. Sodii Chloras (U. S. P.) (NaClO 3 ), 0.5-2 G. (10-30 grs.). The chlorates are colorless prismatic crystals with a saline taste, and are given in solution or in lozenges when used internally. The dry salts form explosive mixtures with organic or other reducing substances, and such mixtures are therefore to be kept cool, and ought not to be ground together, as heat and pressure are liable to cause explosions. Therapeutic Uses. The chlorate of potassium is used chiefly as a mouth wash and gargle in irritable conditions of the mouth and throat, such as aphthe, and in the tenderness and ulceration of the gums and mouth induced by the prolonged use of mercury. It may also be given as a prophylactic to prevent stomatitis when mercury is being prescribed, but it does not prevent the salivation. In catarrh of the throat the chlorate of potassium is often used with apparently good 526 INORGANIC SALTS, ACIDS AND BASES. effects. It has been strongly advised in diphtheria, but is of only questionable value here. The chlorate of potassium is more frequently prescribed than the sodium salt, but the latter seems equally efficient. The chlorates are used in 2-4 per cent, solution, or the official lozenge may be prescribed. In children a somewhat stronger solution with syrup or honey may be used to brush out the mouth, but care should be taken that none is swallowed. The local action of the chlorates has not been explained, and it may be due to the salt-action in part, though not wholly. It has been suggested that they are oxidizing disinfectants, but there is no reason to suppose that they are changed here any more than in the tis- sues in general. It is not impossible that equally satisfactory results might be obtained by the use of the chlorides or nitrates. Chlorate of potassium has been given internally in cases of diphtheria and in some diseases of the mouth, but it does not seem to have any therapeutic value unless when applied locally. Some benefit may arise from its contact with the mouth and throat in the process of swallowing and from its excretion in the saliva. In addition the internal administra- tion of the chlorate is liable to induce dangerous poisoning. It is un- necessary to discuss the earlier uses of the chlorate, which were based on the theory that it gave up its oxygen to the blood, for both theory and practice have been shown to be erroneous. Poisoning. The fatal dose of chlorate varies extremely, as little as 1 G. (15 grs.) having proved fatal in a child, while 40-50 G. (10-12 drs.) have been swallowed by adults without marked symptoms. There is no question that the red blood cells are often peculiarly susceptible to the action of the chlorates ; poisoning is especially common in nephritis. In cases of poisoning the stomach should be evacuated, if any of the salt is believed to remain in it, but the symptoms often appear only 2-3 hours or longer after the drug has been taken. General treatment with central nervous stimulants, ice for the vomit- ing, etc., may be carried out. The formation of methsemoglobin is less liable to occur when the blood is more alkaline than usual, and this has led to the administration of the alkaline carbonates in these cases. After the acute symptoms pass off diuretics are often advised, and large quantities of fluid are given in order to flush out the kidneys and pre- vent as far as possible the tubules from being stopped up by detritus. BIBLIOGRAPHY. Marchand. Virchow's Arch., Ixxvii., p. 455. Arch. f. exp. Path. u. Pharm. t xxii., p. 201 ; xxiii., pp. 273 and 347. Mering. Das chlorsaure Kali, 1885, Berlin. Stokvis. Arch. f. exp. Path. u. Pharm., xxi., p. 169. Cahn. Ibid., xxiv., p. 180. Leurin u. Posner. Centralbl. f. d. med. Wissensch., 1887, p. 354. Dittrich. Arch. f. exp. Path. u. Pharm., xxix., p. 247. Silbermann. Virchow's Arch., cxvii., p. 288. Falkenberg. Ibid., cxxiii., p. 577. Binz. Arch. f. exp. Path. u. Pharm., x., p. 153; xxxiv., p. 185. Jawein. Virchow's Arch., clxi., p. 461. NITRATES. 527 Falck. Pfliiger's Arch., xlv., p. 304. Dreser. Arch. f. exp. Path. u. Pharm., xxxiv., p. 204. (lodates, Bromates.) Kerry u. Host. Ibid., xxxix., p. 144. (Perchlorates.) Mathews. Amer. Journ. of Physiol., xi., p. 237. X. NITRATES. The nitrates are generally supposed to have little action except that of salts in general, and have been comparatively seldom the subject of pharmacological examination. In small doses they induce changes very similar to those seen after the chlorides, but there is little doubt that in addition to the salt-action, a distinct nitrate-ion effect exists, and is manifested chiefly in irritation of the mucous membranes which are exposed to it. Symptoms. The nitrates have a cool, saline taste, and in small doses induce no symptoms save an augmented flow of urine. Large quantities, however, cause gastro-intestinal irritation, giving rise to pain in the stomach region, nausea, vomiting and sometimes diarrhrea, and blood may be present in the vomited matter and in the stools. The urine is often abundant, but may be scanty or entirely suppressed. These symptoms may be followed by great muscular weakness, apathy, collapse and eventually coma and death. At the autopsy the stomach and intestines are found red and con- gested, and very often contain blood extravasations. The kidney is said to have presented the symptoms of acute nephritis and haemor- rhages in some cases of poisoning. When dilute solutions of the nitrates are used, much less irritation is induced, and in fact large quantities may be taken thus without causing any symptoms whatever except diuresis. Action. Very similar effects may be induced by large quantities of common salt, or of potassium chloride, and it is therefore often stated that the nitrates act in the same way as the chlorides. But this is not entirely correct, for while there is no question that the salt-action ex- plains much of the effect of the nitrates, these salts have a specific irritant action. Thus very much smaller quantities of the nitrates than of the chlorides are sufficient to induce serious irritation, and solutions of the nitrates isotonic with the blood induce irritation and congestion in the intestine and are slowly absorbed. This irritant effect of the nitrates has been explained by Binz and Barth as the result of the reduction of the nitrates to nitrites in the alimen- tary canal and tissues, but no symptoms of nitrite action seem to have been observed in cases of poisoning with nitrates. Haldane has recently shown that nitrite is formed from the nitrate used in the preservation of meat by salting, and that some nitrous-oxide haemoglobin is formed and gives a bright red color to the meat. The presence of this pigment may perhaps explain the red color of the intestine in some cases of poisoning in which extravasations of blood are not marked. 528 INORGANIC SALTS, ACIDS AND BASES. The nitrates have long been used as diuretics, more especially th nitrate of potassium. The diuresis is generally attributed to the salt action, but there may be in addition a true stimulation of the kidne; similar to that observed under the action of many other drugs whicl are irritant to the bowel. If WeyPs statement be correct that th nitrates of the urine are not increased by the administration of nitrate by the mouth, the diuresis must be due to some stimulant action onlj The nitrate of potassium is generally considered a better diuretic thai the sodium salt. The Fate of the Nitrates in the Body is still unknown, and in fac seems to vary in different animals and under different conditions. I: man and in most animals, some nitrate is present in the urine normally apparently derived from vegetable food, although it may in some case be one of the final products of the proteid metabolism. Large dose of nitrates given by the mouth lead to some increase in the nitrate ii the urine, although more than half of that ingested disappears entirel in the tissues. Nitrite has also been found in the urine after larg quantities of nitrates in animals and the nitrite reaction is obtained froc a number of organs. When smaller amounts of nitrate are swallowe< (13 G. in man), no increase in the nitrate of the urine is observed the whole of that ingested being changed to some other form in th tissues. It is surmised that the nitrate is reduced first to the nitrite and then to ammonia, or that it is eventually excreted by the lungs a free nitrogen. Some of the nitrate seems to be excreted in the saliv and perspiration, possibly unchanged, although it is rapidly reduced t nitrite in these secretions, and may in fact be changed to this form i the secretory cells. The action of the nitrates on the individual organs is practicall entirely unknown. They have a weak ha?molytic effect in th blood. Richet has found solutions of the nitrate of sodium less harmful t fish living in it than those of any other salt except the chloride. PREPARATIONS. Potasii Nitras (U. S. P., B. P.), Nitre, Saltpetre (KN0 3 ), 0.3-2 G. (5-3 grs.). Sodii Nitras (U. S. P.), Chili Saltpetre (NaNO 3 ), 0.3-2 G. (5-30 grs.). The nitrates form colorless crystals with a cool, saline taste. They ar very soluble in water and are prescribed in dilute solution. Therapeutic Uses. The nitrates are seldom used now except as in gredients of diuretic mixtures ; e. g., along with digitalis. The nitrat of potassium was formerly employed largely in fevers and in variou disorders of the metabolism, such as rheumatism or gout, but in none oJ these has it been found useful. The nitrates are to be given with can when there is any irritation of the stomach and intestine. Authorities differ as to whether they may be prescribed in irritation of the kidney but in every case they ought to be well diluted. SULPHITES. 529 Paper impregnated with saltpetre is used in asthma by burning it in the sick room, when the pyridine and nitrites relieve the spasms by relaxing the bronchial muscles. Saltpetre may be used in cigars or cigarettes for the same purpose, and the tobacco may contain also the leaves of belladonna or some of its allies, as these have a special action on the bronchial muscle. BIBLIOGRAPHY. Binz et Gerlinfjer. Arch, internal, de Pharmacodyn., ix., p. 441. Littlejohn. Edinburgh Med. Journ., 1885, p. 97. Eoehmann. Zts. f. Physiol. Chem., v., p. 233. Weyl. Virchow's Arch., xcvi., p. 462 ; ci., p. 175 ; cv., p. 187. Rfchet. Comptes rend. d. 1. Soc. de Biol., 1886, xxxviii., p. 486. Heffter. Ergebnisse der Physiologic, ii., 1, p. 112. Haldane. Journ. of Hygiene, i., p. 115. Eost. Arch. f. [Anat. u.j Physiol., 1901, p. 534. XI. SULPHITES. The sulphites, an unimportant group of bodies from a therapeutic point of view, have been shown to have a more poisonous action than many better known salts. They possess fairly strong antiseptic properties, because they withdraw oxygen from organic matter in order to oxidize themselves to sul- phates. Injected into frogs, sulphite of soda causes great muscular weak- ness and depression, and eventually paralysis of the central nervous system, beginning in the brain and descending to the spinal cord. Later, the heart becomes weak and ceases in diastole, and the peripheral nerve terminations and the muscles are paralyzed. In mammals the action is exerted chiefly on the medulla oblongata and the heart. In the dog and cat subcutaneous injection causes nausea, vomiting, restlessnesss and dyspnoea and great muscular weakness, ending in arrest of the respiration, and a little later of the heart. In the rabbit the symptoms consist of dyspnoea, muscular weak- ness without loss of spontaneous movements, and finally death from failure of the respiration and the heart. Much larger quantities are required to poison animals when given by the mouth than when injected subcutaneously, probably because the salt is slowly absorbed from the alimentary tract, and also because some of it is changed to the harmless sulphate before it reaches the blood. Some irri= tation of the stomach is caused from the sulphurous acid being freed by the gastric juice, and this induces vomiting in the dog. Intravenous injection shows that the chief seat of action of the sulphites is the medulla oblongata, in which they depress the respiratory and vasomotor centre 5. The heart is acted on directly apparently, for the pulse is slow, and the muscular walls of the vessels are also weakened. Kionka states that sulphites destroy the red cells of the blood, and that infarcts are formed from their remains in the vessels and lead to haemorrhages in many organs. If large quantities be absorbed rapidly, they prove immediately fatal, but if the respiration be kept up for a short time, recovery may follow, because the poisonous sulphite is changed to the harmless sulphate and excreted. About 96 per cent, of the sulphite absorbed into the blood is oxidized to the sulphate, while some 3 per cent, is excreted in the urine unchanged. The thiosulphate is apparently oxidized with greater difficulty, for Walko found 30-50 per cent, eliminated by the kidneys unaltered. Large doses of sulphites have been taken by man without symptoms of poisoning being induced. Even 30-40 gms. are said to have been swallowed, but in most preparations of sulphite a large proportion of sulphate is pres- int, and it is impossible to state how much sulphite was really contained in 34 530 INORGANIC SALTS, ACIDS AND BASES. these doses. Symptoms of gastric and intestinal irritation have been in- duced by comparatively small quantities, and Kionka found that even smaller doses of sulphite administered daily to animals caused hemorrhages in dif- ferent organs, and accordingly condemns the use of sulphites to preserve meat, wines and vegetables ; in addition they seem to have little effect in preserving meat from putrefaction though they improve its appearance. ^ Sodii Sulphis (XL S. P., B. P.) (Na 2 SO 3 + 7H 2 O), a soluble salt which oxi- dizes to the sulphate in the air, is feebly alkaline and has a cool, saline taste. 0.3-2 G. (5-30 grs.). Sodii Bisulphis (U. S. P.) (NaHSO 3 ) has a disagreeable odor of sulphurous acid, an unpleasant taste and an acid reaction. 1-2 G. (15-30 grs.). Sodii Thiosulphas (U. S. P.) (Na 2 S 2 O 3 + 5H 2 O) is very soluble, has a cool, saline taste and is neutral in reaction. 1-2 G. (15-30 grs.). Solutions of these salts have been used to a limited extent as antiseptic mouth-washes in aphthe, and have been prescribed in some forms of fermen- tation in the stomach. They were formerly reputed to be of benefit in cases of pyaemia from their supposed action as antiseptics in the blood, but have never been shown to be of any real value. BIBLIOGRAPHY. Pfeiffer. Arch. f. exp. Path. u. Pharm., xxvii., p. 261. Kionka. Ztschr. f. Hygiene, xxii., p. 351 ; xli., p. 123. Walko. Arch, de Pharmakodynam., iv., p. 311. Lange. Arch. f. Hygiene, xl., p. 143. Rout u. Franz. Arb. a. d. K. Gesundheitsamte, xxi., p. 312. Altsch'dler. Arch. f. Hygiene, xlviii., p. 114. XII. HYPOPHOSPHITES. The hypophosphites have been used in therapeutics in the belief that they had some special influence on nutrition. They were formerly supposed to be oxidized in the tissues to the phosphates, but this has been shown to be incorrect, as practically the whole of the hypophosphite administered can be recovered unchanged from the urine. No entirely satisfactory work on the effects of these salts on the nutrition has been done, but there is no ground to suppose that they have any further action than the other indif- ferent salts, such as the chlorides. The chief effect of the hypophosphite of iron is undoubtedly due to the metallic ion. PREPARATIONS. Sodii Hypophosphis (NaOPH 2 O) (U. S. P., B. P.), 0.2-0.6 G. (3-10 grs.). Potassii Hypophosphis (KOPH 2 O) (U. S. P.), 0.2-0.6 G. (3-10 grs.). Calcii Hypophosphis (Ca(OPH 2 O) 2 ) (U. S. P., B. P.), 0.2-0.6 G. (3-10 grs.). Ferri Hypophosphis (Fe 2 (OPH 2 O) 6 ) (U. S. P.), 0.2-0.6 G. (3-10 grs.). AcidumHypophosphorosum (U. S. P.), 0.5 c.c. (8 mins.). Syrupus Hypophosphitum (U. S. P.) contains the hyphophosphites of cal- cium, potassium, sodium, free hypophosphorous acid, spirit of lemon and sugar, 4-8 c.c. (1-2 fl. drs.). Syrupus Hypophosphitum Compositus (U. S. P.) contains, in addition to the constituents of the above, iron, manganese, quinine, strychnine, and sodium citrate. 8 c.c. (2 fl. drs.). Therapeutic Uses. The hypophosphites are used in weakness and ca- chexia, and especially in commencing phthisis and anemia. The syrup with or without iron is the form in which they are invariably prescribed. There is a popular belief that they improve digestion and nutrition, but most re- liable investigators deny that they have any other influence than the better known and cheaper salts of iron, calcium, etc. SALINE CATHARTICS. 531 BIBLIOGRAPHY. Paqudin et Joly. Comptes rendus de 1'Acad. d. Science, Ixxxvi., p. 1505. Taylor. Lancet, 1861, ii., p. 517. Boddaert. Arch. d. Pharmacodynam., ii., p. 195. Gamier. Kev. Med. de Test, 1896, p. 257. XIII. SALINE CATHARTICS, Dilute solutions of such salts as the chlorides, iodides and bromides of the alkalies are absorbed rapidly from the alimentary canal, but some of the other salts of these metals apparently permeate the epi- thelium with greater difficulty, and their solutions therefore remain unabsorbed for a longer time in the intestine. Little is known of the effects of these salts in the tissues, but their action in the intestine has led to their therapeutic use, and they may therefore be classed to- gether as the saline cathartics, in order to distinguish them from the rapidly absorbed salts, such as the chlorides, or bromides. The chief salts of sodium and potassium which have this intestinal action are the sulphates, phosphates, tartrates and citrates ; less known ones are the malates and ferrocyanides. It is manifest that the peculiar effect of these salts is due to the acid constituent, or anion, and not to the base or kation, for the latter may be present in readily absorbable salts, such as chlorides. All combinations in which the sulphate, phosphate, etc., ion is found, therefore, are less easily absorbed than the corresponding ones with bromide or chloride ions. But these cathartic anions are only weakly active, and no pronounced difference can be observed in the action of chlorides and sulphates, unless the salt can be given in large quanti- ties, as is possible in the case of the salts of the alkalies. The effects of the sulphate and hydrochlorate of morphine, for example, may be taken as identical, because the anion is present in so small amount as to be practically inert. The chloride ion is rapidly absorbed, as is seen in the case of sodium chloride. Yet when the chloride of magnesium is administered, it disappears only very slowly from the bowel. It would seem, there- fore, that the magnesium is also more slowly absorbed than the sodium and potassium ions, and that cathartic action can be obtained from either basic ions (kations) or from acid ions (anions). When both ions of a salt are slowly absorbed, the cathartic is, of course, more power- ful than when one is rapidly absorbed. Thus, magnesium sulphate is a more powerful purgative than either magnesium chloride or sodium sulphate, because in the first both ions are difficult of absorption, while in the others only one is cathartic. It seems probable that all the alkaline earth ions resemble magnesium in permeating the epithelium with difficulty. The chief saline cathartics used in therapeutics are the sulphate of sodium (Glauber's salt), the sulphate of magnesium (Epsom salt), the double tartrate of sodium and potassium (Rochelle salt) and the ci- trates of potassium and magnesium. In addition the oxide and car- 532 INORGANIC SALTS, ACIDS AND BASES. bonate of magnesium have some purgative action from being formed into soluble salts in the stomach and intestine. But besides these many other salts are slowly absorbed and might therefore be used for this purpose. Thus the sulphates, citrates, or tartrates, of any of the alkalies or of the non-poisonous alkaloids might be used for this purpose, provided they are soluble, and any of the magnesium salts might be used in the same way. Symptoms. The external application of solutions of the saline cathartics has the same effect as that of any other indifferent salt, such as sodium chloride (see page 491). Most of the cathartics have a harsh, bitter, unpleasant taste, and when taken in concentrated solution, may induce some nausea, partly from the taste, and partly from their effect on the stomach, which is the same as that of solutions of sodium chloride of similar concentra- tion. Dilute solutions, however, provoke no such symptoms, but after one or two hours induce a profuse watery evacuation of the bowels. This is sometimes preceded by some pain and griping, but these are not nearly so frequent or so severe as after the vegetable purgatives. Not infrequently the urine is increased in amount afterwards, or it may be found to have an unusually high percentage of salts. If a moderate quantity of a dilute solution be given, only one evacuation follows, but large doses of concentrated solutions induce repeated stools, which at first contain some faecal matter, but later consist mainly of bile-stained mucous fluid. Action : Intestine. The explanation of the action of the saline cathartics has been much debated, and the details have not even yet been entirely settled. One point is, however, perfectly certain the saline cathartics differ from the vegetable purgatives in not inducing irritation of the intestine, unless when they are given in very large quantities. The characteristic effect is not irritation, but retarded ab- sorption. If a solution of sodium chloride isotonic with the blood serum be administered by the mouth to a dog with a caBcal fistula, little or none of it reaches the wound, as it is all absorbed in the stomach and small intestine. If, on the other hand, an equal amount of an isotonic solution of sodium sulphate be administered in the same way, the most of the solution escapes by the fistula, only some 10-20 per cent, having been absorbed by the stomach and small in- testine. In a normal dog or in the human subject, much larger amount of fluid therefore reaches the large intestine if sodium sulphate be dissolved in it than if sodium chloride be used instead. The con- tents of the large intestine are consequently more fluid than usual, and are passed down more easily towards the rectum. At the same time the weight and distention of the bowel induces increased peristalsis and the whole is evacuated. This increased peristalsis is due, how- ever, not to any irritant action such as has been found to be induced by rhubarb or croton oil, but to the large amount of fluid contents. If a weaker solution of sodium sulphate is administered, the only difference is that more of the fluid is absorbed and less reaches the SALINE CATHARTICS. 533 large intestine ; but however weak the solution, more of it reaches the large intestine than if a correspondingly weak solution of common salt had been given. If a hypertonic solution be administered, the effect is somewhat different. The salt is still unabsorbed, but it draws fluid from the blood into the bowel from its having a higher osmotic pressure than the blood. A similar draining of the body fluids occurs when con- centrated solutions of common salt reach the bowel, but the cathartic salts are much more powerful, because they do not pass out of the bowel into the blood so easily. Instead of an exchange of salt and fluid being carried on by the blood and intestinal contents, the blood gives up its fluid without any sufficient compensation in salt. Eventually the intestinal fluid becomes isotonic, and then some absorption of both salt and fluid occurs ; in fact, some salt has been absorbed all along, as the epithelium is not absolutely impermeable to the cathartics. But much less of the sulphate is absorbed than of the chloride given in equal concentration, and as a general rule a strong solution causes such an accumulation of fluid that the bowel becomes distended and evacuates its contents. If, however, from any cause this fails to occur, a gradual absorption follows and the whole of the salt and fluid in the bowel is absorbed. These salts may fail to purge, for example, when the blood and tissues contain very little fluid, as in animals which have been deprived of water for several days previously. In this case the osmotic pressure in the bowel is unable to draw fluid from the concen- trated blood, which on the other hand has a higher attraction for the fluid in the bowel than usual. But where large quantities of fluid are present in the tissues, as in oedema and dropsy, the saline cathartics drain them through the blood into the bowel, and very profuse evacu- ation occurs, with the disappearance of the exudate. There is still some doubt as to why the saline cathartics are so slowly absorbed from the intestines, but the most widely accepted view is that they fail to penetrate into the cell, exactly as the salts of the metals fail to penetrate the red blood cells, that there is a distinct affinity between the bowel epithelium and the chloride of sodium, but only a much weaker one between it and the cathartics, which therefore fail to permeate it. The acceptance of this view does not involve the rejection of the belief that the cell is actively engaged in absorption, for it is difficult to explain how a solution after penetrating the superficial layers of the epithelium is passed on from them to the blood except by assuming that the cell exercises some propelling force, which maybe exerted only during its life. The further question arises, why the intestinal epithelium should be permeable by certain salts such as the chloride of sodium and imper- meable by others (sulphate of sodium). In this relation it has been found by Hofmeister and Pauli that the purgative salts have a greater tendency to precipitate proteids and have less tendency to permeate into unorganized colloids than most of the non-purgative salts. In numer- ous other instances the sulphates, tartrates, and other cathartic anions have proved slower in permeating into living cells than the chlorides 534 INORGANIC SALTS, ACIDS AND BASES. and bromides, and their effects on the blood cells, muscle, nerve, and some other tissues show marked deviations from those of the halogen salts. It is impossible to determine at present how far the action of these anions is explained by their slow permeation and how far a more specific action is involved, but there can be no question that the former factor is the predominant one in many of these reactions. Another curious relation between the purgative anions is that their calcium salts are all very much less soluble than those of the salts which pene- trate the epithelium, but whether this is merely a coincidence or not is uncertain. Most of the cathartic anions are ' bivalent or trivalent, but this is not true for all of them, for the higher members of the acetate series are absorbed with the greatest difficulty by the intestine. The saline cathartics induce certain changes in the Blood indirectly through their action on the intestine. They prevent the absorption of the fluid of the food, or, if in sufficient concentration, actually draw fluid from the blood and tissues into the bowel, and under both condi- tions the blood becomes more concentrated than usual ; in the first case because it is not reinforced by the usual amount of fluid from the food, in the second because it actually loses fluid into the intestine. This concentration of the blood leads to a sensation of thirst, and to a lessened excretion of fluid by the kidneys and other glands. A certain amount of salt and of fluid is absorbed from the intestine, unless purgation follows very rapidly, and this salt acts in the blood and tissues in the same way as the salts which do not act as cathartics. When very dilute solutions of these salts are given, therefore, the effect is similar to that of ordinary salt, except that the hydrsemia and the diuresis do not follow so soon, because the absorption is somewhat slower. Stronger cathartic solutions at first cause a concentration of the blood and lessened urine, but afterwards the excess of salt in the blood may cause diuresis. The greater the purgative action, the less the diuretic, because more fluid and more of the cathartics are thrown out in the stools. If no purgation follows for any reason, as when the blood has been concentrated by long abstinence from water, the whole of the salt eventually passes into the blood and is excreted by the kid- ney, and may cause very considerable diuresis and a still further con- centration of the blood. The sulphates are absorbed by the epithelium of the renal tubules with much greater difficulty than chloride, and thus offer osmotic resistance to the absorption of the fluid in the tubules ; sulphates absorbed into the blood therefore induce a more diffuse diuresis than an equal amount of chloride, but less of the former reaches the blood generally, so that the chlorides are better practical diuretics. From the above it can be at once inferred that a saline cathartic in- jected intravenously causes no purgation, for instead of preventing the passage of fluid from the bowel into the blood, it rather encourages its absorption by increasing the osmotic pressure of the blood. And this has been shown to be the case by repeated experiment. One fact which seems to be opposed to this explanation is that the saline cathartics sometimes cause purgation when injected in very small quantity into SALINE CATHARTICS. 535 the subcutaneous tissues of the abdomen. But this is due not to the specific action of the drug, but to its causing pain and inflammation, and in fact acting as a counter-irritant (Hay). The statement is sometimes made that the saline cathartics act as cholagogues, i. e., increase the secretion of bile, but this has been shown to be erroneous by a series of careful observations. The Temperature is often somewhat reduced by the action of the saline cathartics, but seldom more than one half degree. The habitual use of saline cathartics is often efficient in Reducing the Weight in obesity, and many of the natural mineral waters have a considerable reputation in the treatment of such cases. The way in which they act is not understood, for though there is often somewhat less proteid and fat absorbed from the intestine, this appears too small to account for the loss in weight. There seems no reason to suppose that any marked change in the nitrogenous metabolism is induced by the cathartics, for the nitrogen in the urine is often practically unal- tered in amount. The only remaining explanation of the efficiency of these salts in obesity is that they increase the oxidation of the fats of the body, presumably by altering the movements of the body fluids. This, however, is only a surmise which as yet is unsupported by known facts. When purgation follows the administration of a saline cathartic, the most of the salt escapes in the faeces, never having been absorbed at all. When the salt fails to purge, however, and is absorbed, it undergoes the usual exchanges in the tissues and is excreted by the urine. There is no reason to suppose that any of it appears again in the stomach or intestine. The Sulphates seem to pass through the tissues without injuring them, and but little effect is observed from injecting considerable quantities into the blood. When the sulphate ion is combined with a poisonous base such as potassium oT magnesium, the injection is of course followed by character- istic symptoms; but the anion seems to be comparatively harmless. The Phosphates are also very inactive after absorption. Garngee found the orthophosphate quite harmless, while the metaphosphates and pyrophosphatea are poisonous, more especially the last, when injected subcutaneously or intra- venously. Phosphates absorbed in man and in the carnivora are excreted by the kidney and increase the acidity of the urine ; in the herbivora they are excreted exclusively by the bowel wall. The Citrates are rapidly oxidized in the tissues to carbonates, and only traces of the unchanged salt escape in the urine. The urine may thus be rendered alkaline by the administration of the citrates, especially in small quantities which are insufficient to induce purgation (see hydrates and car- bonates of the alkalies, page 544). The Tartrates are more slowly oxidized, and a considerable quantity is excreted in the urine unchanged. 1 Injected into the blood directly, the citrates and tartrates seem to act as heart poisons, but very little is known in 'regard to this point. The Magnesium Salts first accelerate and then weaken and paralyze the heart and depress the central nervous system, when they are injected into the blood, but induce no symptoms when they are absorbed from the intes- tine, as they are probably rapidly excreted by the kidneys. The magnesium of the urine is certainly increased by the administration of the salts by the mouth, especially if they fail to purge, but it is possible that some of the mag- nesium is excreted by the bowel, and it has been recently suggested that it 536 INORGANIC SALTS, ACIDS AND BASES. may appear in the milk. In the frog the salts of magnesium are said to paralyze the striated muscles in the same way as those of potassium, but no such effect is induced in mammals even by intravenous injection, the animal dying from the action on the heart and nervous system before the muscular action is elicited. The oxide and carbonate of magnesium differ from the other saline cathartics in being very insoluble and in possessing an alkaline reac- tion. Part of that ingested is formed into magnesium chloride in the stomach, however, and the carbonic acid present in the intestine may dissolve part by forming the bicarbonate. Their alkalinity serves to remedy any excessive acidity of the stomach or intestine, while at the same time they are mildly cathartic. (See page 541.) The prolonged use of large quantities of magnesia has in some cases led to the forma- tion of large concretions in the bowel, resulting in obstruction, PREPARATIONS. SODII SULPHAS (U. S. P., B. P.), Glauber's salt (Na 2 SO 4 , 10H 2 O), soluble in about 3 parts of cold water, 2-30 G. (30 grs.-l oz.). MAGNESII SULPHAS (U. S. P., B. P.), Epsom salts (MgSO 4 ,7H 2 O), soluble in H parts of cold water, 2-30 G. (30 grs.-l oz.). Potassii Sulphas (U. S. P., B. P.), 1-4 G. (15-60 grs.). These are crystalline salts with a harsh, bitter taste. SODII PHOSPHAS (U. S. P., B. P.) (Na 2 HPO 4 + 12H,O), soluble in about 6 parts of cold water, 1-30 G. (15 grs.-l oz.). Sodii Pyrophosphas (U. S. P.) (Na 4 P 2 O 7 + 10H 2 O), 1-20 G. (15-300 grs.). These are crystalline salts with a cool, saline taste. Liquor Sodii Phosphatis Compositus (U. S. P.) contains sodium nitrate and citric acid. Dose, 8 c.c. (2 fl. drs.). Sodii Phosphas Exsiccatus (U. S. P.), dried sodium phosphate, 1 G. (15 grs.). Potassii Bitartras (U. S. P.), Potassii Tartras Acidus (B. P.), cream of tartar (KHC 4 H 4 O 6 ), 1-4 G. (15-60 grs.). POTASSII ET SODII TAB/TEAS (U. S. P.), SODA TARTARATA (B. P.), Rochelle salt (KNaC 4 H 4 O 6 + 4H 2 O), soluble in 1.4 parts of cold water, 8-16 G. (120- 240 grs.). Potassii Tartras (B. P.) ((CHOH) 2 (COOK) 2 H 2 O), 30-240 grs. Potassii Citras (U. S. P., B. P.) (C 3 H 4 OH(COOK) 3 ), 1-3 G. (15-45 grs.). Lithii Citras (U. S. P., B. P.) (C 3 H 4 OH(COOLi) 3 4H 2 O), 0.3-0.6 G. (5- 10 grs.). Sodii Citras (U. S. P.) (2C 3 H 4 OH(COONa) 8 -f 11H 2 O), 1-3 G. (15-45 grs.). These form salts with a cool saline, or, in the case of the bitartrate, acidulous taste. They are all very soluble in water, except the bitartrate. The citrates are not purgative in the dose given. MAGNESII OXIDUM (U. S. P.), MAGNESIA LEVIS (B. P.), light or calcined magnesia (MgO). MAGNESIA PONDEROSA (B. P.), MAGNESII OXIDUM PONDEROSUM (U. S. P.), heavy magnesia (MgO). MAGNESII CARBONAS (U. S. P.) ((MgCO 3 ) 4 Mg(QH) 2 + 5H 2 O). MAGNESII CARBONAS LEVIS (B. P.) ) rafMeCO ^ MirfOm 4H O) MAGNESII CARBONAS PONDEROSA (B. P.) ) (l M u s)' M St u These all form white amorphous powders with an earthy, not saline, taste. They are insoluble in water, but the carbonate is dissolved by excess of car- bonic acid. 0.3-4 G. (5-60 grs.V Liquor Magnesii Carbonatis (B. P.), fluid magnesia, contains 2 per cent, of carbonate of magnesia dissolved by the presence of carbonic acid. 1-2 fl. oz. SALINE CATHARTICS. 537 Effervescing Preparations. PULVIS EFFERVESCENS COMPOSITUS (U. S. P.), PULVIS SOD.E TARTARAT^; EFFEBVESCENS (B. P.), Seidlitz powder. This powder is made up in two papers, of which the blue one contains a mixture of 3 parts of Rochelle salt and one part of sodium bicarbonate, in all 10.4 G. (160 grs.), while the white paper contains 2.25 G. (38 grs. B. P.) of tartaric acid. When the powders are dissolved separately in water and the solutions mixed, the tartaric acid acting on the bicarbonate releases carbonic acid with effervescence. Liquor Magnesii Citratis (U. S, P.) is a solution of magnesium citrate with excess of citric acid to which potassium bicarbonate is added. The whole is bottled tightly and effervesces when the cork is removed. 150-400 c.c. (5-12 fl oz.). Lithii Citras Effervescens (U. S. P., B. P.), a mixture of lithium carbonate or citrate with sodium bicarbonate, and citric acid (and tartaric acid, B. P.). 4-8 G. (60-120 grs.). Magnesii Sulphas Effervescens (B. P., U. S. P.), a mixture of Epsom salts, sodium bicarbonate, tartaric and citric acids, which effervesces when mixed with water. 60-240 grs. for repeated administration ; for a single administration -1 oz. Sodii Sulphas Effervescens (B. P.), a similar mixture containing the sulphate of soda instead of that of magnesia. 60-120 grs. for repeated administration ; for a single administration | J oz. Sodii Phosphas Effervescens (B. P., U. S. P.), similar to the above, but con- taining the phosphate in place of the sulphate. Dose as for the effervescent sulphate. Sodii Citrotartras Effervescens (B. P.), a mixture of sodium bicarbonate with tartaric and citric acids. It is not purgative in the dose advised in the B. P. 60-1 20 grs. Many other effervescent mixtures are used instead of the official ones among them the tartrates and citrates of the alkalies, the acetate of mag- nesium, etc. The sulphates of sodium and of magnesium, the tartrates of sodium and potassium and the phosphate of soda are given in solution, the last often in milk. Unless under special conditions the salts ought not to be in greater concentration than 5-10 per cent. Magnesia and magnesium carbonate are administered in powder, sweetened if necessary. The effervescent prepara- tions are always to be taken in solution in about a tumbler of water ; in some instances in which this was not understood, severe distention of the stomach with alarming symptoms have arisen from the carbonic acid being freed in the stomach. The effervescent preparations ought to be kept dry, and the solution of magnesium citrate has to be kept tightly corked. Very often the natural mineral waters are used instead of the pharmaco- poeial preparations, the best known purgatives among these being the Hun- yadi-Janos water and Carlsbad water, which contain the sulphates of sodium and magnesium. " Carlsbad salts " are obtained by the evaporation of the waters, but are very often artificial imitations. Many other springs have the same effects, and a widespread belief exists that the natural waters are u more efficient " or " less depressant " or have some mystical virtues that are not shared in by the artificial salts, but this belief does not seem to have any real basis, and is probably a survival of the old religious belief in the healing properties of springs. In the natural waters the purgative salts are always accompanied by other less active ones, such as the chlorides of sodium, calcium, etc. The sulphovinate of sodium (N"aC.,H 5 SO 4 ) has been advised as an aperient, but is much weaker than the others, though it has a more pleasant taste. It is very liable to decompose with the formation of sulphate of soda, and perhaps much of its action may be due to the presence of the latter. 538 INORGANIC SALTS, ACIDS AND BASES. Therapeutic Uses. The saline cathartic^ are very largely used to relieve constipation. Habitual constipation seems to be caused by insufficient peristalsis, and the slow passage of the contents through the intestines allows of a more complete absorption than usual, this in turn rendering the faeces hard and dry and difficult to move onwards. The saline cathartics increase the fluidity of the intestinal contents, and thus facilitate their expulsion, and this is probably the only effect they have when taken in small quantities, and especially in dilute solution as in the natural mineral waters. In larger quantities, however, more water is retained in the bowel, and the weight and distention cause peristalsis, while in sufficient quantity they draw fluid from the blood and cause profuse watery discharges. When a very complete evac- uation is desired, the saline cathartics may be given along with some of the vegetable purgatives. Such mixtures are the official Black Draught (see Senna) and the compound powder of Jalap. The saline cathartics act much more rapidly than the vegetable purgatives, and a common method of combining their effects is to give the latter in the evening and the saline the following morning. The chronic constipation due to sedentary habits is much benefited by the saline cathartics, more especially by dilute solutions taken be- fore breakfast. The sulphates and tartrates are harsh and unpleasant to the taste, and the natural waters are often preferred, or one of the effervescent preparations may be used in those cases. The sulphates and tartrates are more frequently used where a single large dose has to be prescribed in order to empty the bowel, but here also the Seidlitz powder may be advised instead, as being more agree- able to the taste. These cathartics were at one time used in fever, partly from a theory that they reduced the temperature ; they are cer- tainly less liable to cause pain and griping than the vegetable purga- tives, and thus tend to disturb the patient less. The sodium phosphate is often prescribed for children, either as a powder to be given in jelly, or in solution in milk or other food, which completely hides its taste. The saline cathartics are used to lessen intestinal putrefaction, and are sometimes very efficient, though they do not act through any an- tiseptic power, but simply by removing the putrefying mass. The phosphate of soda has been especially recommended in some forms of diarrhoea in children. The saline cathartics are administered to remove accumulations of fluid in the body arising from cardiac or renal insufficiency, or from an old effusion. For this purpose the sulphate of magnesium is used in a large dose, dissolved in about its own weight of water ; if purgation does not follow in 1-3 hours, an enema may be necessary, or the saline may be given along with a vegetable purgative. This form of treatment was very popular at one time, but is liable to weaken and depress the patient, and is specially contraindicated, therefore, in asthenic conditions. Other methods of removing accumulations of fluid are by the use of SALINE CATHARTICS. 539 diuretics (see caffeine, theobromine, page 245), diaphoretics (see pil(x carpine, page 315), or by cardiac remedies (digitalis, page 440). As diuretics the saline cathartics are inferior to other salts, such as the acetates or nitrates. Large quantities of dilute solutions of the purgative salts are of value in the treatment of some forms of obesity, the mineral waters being generally prescribed for this purpose, or the patient being sent to drink them at their source. Magnesia and magnesium carbonate are less liable to purge than the soluble salts, and are specially indicated in hyperacidity of the stomach or in acid putrefaction in the bowel. They cause less irrita- tion than the carbonates of the alkalies because of their insolubility, and at the same time have the advantage of acting as mild purgatives, while the lime preparations which are insoluble, tend to induce con- stipation. The magnesia preparations may be used also in diarrhoea as antacids, as they have no irritant action on the bowel. Freshly prepared magnesia is recommended in arsenic poisoning to form an in- soluble precipitate in the stomach, and in poisoning with acids it is also of value when it can be obtained readily. In both cases it is to be given in large quantities. The phosphate of soda has been given in various bone diseases, as in osteomalacia and rickets, this treatment being founded on the belief that the softening of the bones is due to the lack of phosphates in the food, but there is no reason to suppose that this idea is correct, and the treatment is not attended with success. In cases of exophthalmic goitre the phosphate has been recommended, but no explanation has been given of its action here, and some question exists as to whether it is really of value. 1 It has also been recommended in the uric acid diathesis. The phosphates have been supposed to be of benefit in nervous diseases, on the theory that these were due to the insufficiency of phosphorus in the brain, and glycero-phosphates have been introduced for the same reason, but both theory and practice have proved to be erroneous, for the animal organism is unable to build up proteid combinations from their inorganic constituents. The use of sulphate of sodium in phenol poisoning, which was at one time recommended, has been shown to be quite without effect on the progress of the intoxication. (See Carbolic Acid, page 404.) The ferrocyanide of potassium has been advised in irritant poisoning with iron and copper salts, with the hope that the insoluble ferrocyanides would be formed ; a better treatment, however, is washing out the stomach, and the greater part of these salts is removed by vomiting in any case. BIBLIOGRAPHY. The literature of saline cathartics up to 1884 is discussed by Hay. See also Vege- table Purgatives, p. 108, and Salt Action, pp. 489, 497. Hay. Saline cathartics, Journ. of Anat. andPhys., xvi. and xvii. ; also in mono- graph, Edinburgh, 1884. London. Zts. f. klin. Med., xiii., p. 48. Dapper. Ibid., xxx., p. 371. Arch. f. Verdauungskrank., iii., p. 1. Jacoby. Berl. klin. Woch., 1897, p. 248. Heidenhain. Pfliiger's Arch., IvL, p. 579. K&vesi. Centralbl. f. Physiol., 1897, p. 553. Hamburger. Arch. f. Anat. u. Phys., 1896, p. 428. Hober. Pfliiger's Arch., Ixx., p. 624. Flemming. Inaug. Diss., Dorpat, 1893. 540 INORGANIC SALTS, ACIDS AND BASES. Wallace and Cushny. Am. Journ. of Physiol., i., p. 411. Pfliiger's Arch., Ixxvii., p. 202. Gamgee, Priedley and Larmuth. Journ. of Anat. and Phys , xi., p. 255. (Phosphates.) Bergmann. Arch. f. exp. Path. u. Pharm., xlvii., p. 77. Swiatecki. Ztschr. f. phys. Chem., xv., p. 49. XIV. HYDRATES AND CARBONATES OF THE ALKALIES. The hydrates and carbonates of potassium, sodium and lithium owe their pharmacological action entirely to the non -metallic ion, which is so much more powerful than the metal that the latter may be dis- counted. In the hydrates the active constituent, then, is HO. The carbonates and bicarbonates dissociate into K- or Na- ions and CO 3 , but the latter rapidly combines with the hydrogen of the water and thus frees OH, so that the final effect is the same as if a hydrate had been administered, except that the carbonates are less rapidly dis- sociated than the hydrates, and, less OH being formed, are less violent in their action. This hydroxyl ion, then, is what induces the alkaline reaction of the solutions and their pharmacological effect, the metallic ion only serving as a means of applying the hydroxyl ion, but not affecting the pharmacological action. In other words the alkalinity (hydroxyl ion) of the hydrates and carbonates determines their action ; the metal has no practical importance. It is therefore erroneous to take the hydrates and carbonates as typifying the action of potassium or sodium, for in these the metallic action is much less distinct than in the chlorides, the Cl ion being practically inert, while the hydroxyl is exceedingly poisonous. It may be remarked in passing that the importance of the reaction be- tween alkalies and acids lies not in the combination of the metal with the anion of the acid, but in the combination of the powerful hydroxyl ion with the hydrogen ion of the acid. In the effects of potassic hydrate in the stomach, the main importance is to be attached not to the potassic chloride formed but to the water (K HO + H Cl = K C1 + H 2 O), for the potas- sium and chloride ions remain unchanged by the operation while the hydroxyl and the hydrogen ions disappear. Action. The pharmacological action of this group is due to their powers of neutralizing acids and of dissolving proteids and changing them to alkali-proteids, and in a less degree to their saponifying fats. They have in addition the ordinary salt-action, and in concentrated solutions withdraw fluid from the tissues. The solution of proteids by the alkalies and the characters of the compounds thus formed outside the body are well known and need not be entered into here. The same solvent action is observed in the living tissues whenever the hydrates and carbonates come in contact with them in sufficient concentration. The hydrates are, of course, much more powerful solvents than the carbonates, and these than the bicar- bonates. In very dilute solutions this solvent action is exercised only on the superficial tissues, but when stronger solutions are used, or when even weak solutions remain long in contact with the tissues, they tend to penetrate more deeply and cause widespread destruction or corrosion. These bodies form soluble compounds with the proteids HYDRATES AND CARBONATES OF THE ALKALIES. 541 and are only slowly neutralized by the tissues, so that no such bar- rier is raised against their penetration as is met by some other corrosives. Applied to the Skin weak solutions dissolve the superficial layer of horny matter and the oily secretions of the glands, and thus cleanse the surface more thoroughly than water or solutions of neutral salts. When applied for some time, they penetrate more deeply and cause some slight irritation and redness. Concentrated solutions dissolve the skin and cause necrosis of the deeper tissues, generally covered by a semitransparent crust which falls off in the course of a few days, leaving an ulcer. The solutions of the carbonates are much less corrosive than those of the hydrates, and induce actual lesion of the skin only under exceptional circumstances, such as very prolonged application. In the Mouth the hydrates and carbonates have a characteristic " alkaline " taste, and dissolve the superficial layers of the lining mem- brane and the mucus of the secretions. The lips, tongue, and gums assume a bright red color from the irritation and feel soapy to the touch. Concentrated solutions may cause deep corrosion, as in the skin, while very weak solutions have no effect except the characteristic taste and a reflex flow of saliva. The corrosion caused by strong solu- tions extends to the throat and O3sophagus, and may either prove im- mediately fatal or may give rise to cicatrices subsequently. The effect of the hydrates and carbonates in the Stomach has been much disputed, and even now it is impossible to explain some of the therapeutic results. Small quantities are undoubtedly neutralized by the hydrochloric acid of the gastric juice and act no longer from their alkalinity, but merely from their effects as salts, if at all. Larger quantities render the contents of the stomach neutral or alkaline and thus prevent gastric digestion. Very concentrated solutions corrode the walls of the stomach and may prove immediately fatal from caus- ing perforation into the peritoneal cavity, while if the corrosion is not so severe, and the patient recovers from the shock and collapse, gastric ulcer and cicatrices may result. It is very frequently stated that alkalies and alkaline carbonates in- duce a more rapid secretion of the gastric juice. In fact, some writers go so far as to assert that it is impossible to render the contents of the stomach alkaline except by the use of poisonous doses, because the gastric juice is so rapidly augmented by the alkalies. This belief seems to be founded on the old aphorism contraria contrariis stimulan- tur } which proves to have no greater basis in fact than other similar dogmas. It has been demonstrated experimentally in dogs that alka- line carbonates, whether given by the mouth or injected into the stomach through a gastric fistula, do not influence the amount of the gastric secretion, and Reichmann has recently shown that in man dis- tilled water increases the free acid and the chlorides of the stomach contents as much as an equal amount of an alkaline solution. The 542 INORGANIC SALTS, ACIDS AND BASES. only satisfactory examinations of the question, therefore, show that the alkalies have no effect whatsoever on the activity of the secretory glands of the stomach. On the other hand, they may affect the juice already secreted by making it neutral or even alkaline, and may thus render it entirely useless for digestion and disinfection. Of course in hyperacidity of the stomach, tlje alkalies may be of benefit by lessen- ing the amount of free acid present. Dilute solutions of the alkalies may act as slight irritants to the stomach wall and thus improve its circulation, and lessen pain, eruc- tation and distention, very much in the same way as other slight gas- tric irritants, such as the volatile oils. In the case of the carbonates and bicarbonates, this carminative action may be strengthened by the carbonic acid liberated by the hydrochloric acid. In addition, they tend to render the mucus less tenacious, or may dissolve it completely, and thus improve the condition of the stomach. Nothing is known as to their effects on the movements of the stomach, or on its power of absorption, but if carbonic acid be liberated, it tends to increase the movements to some extent. In the small Intestine the alkalies have been shown to have an in- direct effect, through their diminishing the acidity of the gastric juice. The secretion of the pancreas is normally stimulated by the passage of an acid fluid through the pylorus, and if the acidity of this fluid be reduced by the administration of alkalies, a much smaller quantity of pancreatic juice is thrown into the intestine. This may again render the digestion less complete, although the greater alkalinity of the intestinal contents tends to increase the efficiency of the pancreatic juice already secreted. On the other hand, in cases of hyperacidity of the stomach, the administration of alkalies may render the contents of the intestine less irritant, and thus tend to allay catarrh. The alkalies administered in medicinal doses seem to have no effect on the intestinal putrefaction, for the double sulphates of the urine remain unchanged in amount. Kast states that very large quantities (15 G., | oz.) increase the putrefaction, probably through neutralizing the disinfectant gastric juice. The alkalies have been believed to have some special action on the Secretion of Bile ; thus, it has been supposed that they rendered the bile more alkaline and tended to dissolve the mucus contained in it, that they prevented the deposition of, and even dissolved gall-stones, or that they increased the secretion of bile and thus swept them out of the gall-bladder. All of those theories have been overthrown by the investigations of Stadelmann and his pupils, who have shown that alkaline salts do not increase the secretion of bile, are not excreted in it, and do not cause any change in its reaction. Any effect which the alkaline carbonates or hydrates may possess in hepatic diseases would therefore seem due to their effects in the duodenum. The prolonged administration of very large doses of the alkaline car- bonates and bicarbonates causes chronic gastro-enteritis in animals, is said to have proved fatal to them in some instances, HYDRATES AND CARBONATES OF THE ALKALIES. 543 The hydrates are probably Absorbed in combination with proteids or as carbonates. Both hydrates and carbonates disappear rapidly from the stomach and intestine, although the bicarbonate of soda is some- times credited with some laxative action ; this may not, however, be due to the same causes as in the case of the saline cathartics. The absorption of these bodies leads to an increase in the alkalinity of the blood and tissues. Even when the alkali administered has been neu- tralized by the gastric juice, the body is rendered more alkaline, be- cause a certain amount of the carbonate of the blood and tissues is spared, which would normally have been used to neutralize the hydro- chloric acid before it could be reabsorbed. This condition of aug- mented alkalinity can only last a short time, however, as the excretory glands at once proceed to remove the excess. But this transient in- crease in the alkalinity of the tissues has been supposed to influence the Metabolism very considerably. It is found that outside the body certain bodies undergo oxidation much sooner in alkaline solution than when neutral ; the example most frequently cited is pyrogallol, which combines with oxygen much more rapidly in the presence of alkalies. From this it has been surmised that an increase in the alka- linity of the fluids of the body must be followed by an acceleration of the metabolism. A large number of researches made on man and ani- mals in regard to this point have given varying results, but tend on the whole to show that the alkalies have less effect on the tissue- change than was formerly believed. The investigators of the subject have generally confined their attention to the effects of alkalies on the products of metabolism excreted in the urine, and have found the total nitrogen excreted to be unchanged in a considerable number of in- stances, to be slightly increased in others, and to be diminished in a few individuals. Even in those cases in which an increase is observed in the nitrogen of the urine, it does not always indicate an increase in the nitrogenous metabolism, for the urine is often increased consider- ably and it is evident that the interchange of the fluids of the tissues and blood is augmented ; so that the increased nitrogen of the urine is accounted for by the tissues being more thoroughly flushed out than usual by the alkalies, which act in the same way as the neutral salts. (See page 494.) The effect of the alkalies on the total nitrogen ex- cretion seems to vary considerably with the individual, and in one and the same person different effects have been noted from two salts which exist in the blood in the same form. Although the total nitrogen may be little affected by the administra- tion of the alkalies, the form in which it is combined in the urine and in the blood may be changed. The ammonia of the urine is often diminished in amount, while the urea excretion is correspondingly aug- mented. This is especially marked in cases in which excess of acid is formed in the tissues or absorbed in any way, and is explained by the fact that this acid is ordinarily neutralized by the formation of ammo- nia in the tissues (see Acids). When, however, fixed alkali is present in sufficient amount, as when the carbonates are given, the nitrogen 544 INORGANIC SALTS, ACIDS AND BASES. which would otherwise have been excreted as ammonium salts, is formed into urea. The Uric Acid Excretion under the alkalies has been the subject of numerous researches, but in the great majority of these very imperfect methods of estimation have been used. In the few cases in which satisfactory methods have been employed, the results have been diver- gent, the uric acid being sometimes decreased and sometimes increased by the alkalies. In any case the change is trifling in extent, and no inference can be drawn as to the uric acid metabolism from it. As regards the Oxidation in the Tissues, one observer found the oxy- gen absorbed and the carbonic acid excreted by the lungs increased by the alkalies, while another could detect no change. Another method of estimating the activity of the oxidation in the tissues has been used by Taniguti and Jawein, who both found that in man the neutral sul- phur of the urine is increased by the alkalies at the expense of the acid sulphates ; they interpret this as indicating a diminution of the oxidation of the tissues. On the other hand, Heifter and Harnack, using the same method, came to the conclusion that the oxidation in the tissues of the dog was increased by the alkalies, and this accords with Munk's observation that a diminution of the alkalinity of the blood of the horse lessened the oxidation of phenol. The only conclusion which seems admissible from these laborious investigations, is that the tissue waste is but little affected in amount by the increased alkalinity of the blood, and the slight changes ob- served may vary not only in different species, but in different individ- uals, and even in the same individual at different times. The cause of this individual variation may be differences in the amount of acid formed in the tissues, but may also be differences in the local effect of the alkalies in the alimentary tract. The organism rapidly frees itself from the excess of alkali by Ex- creting alkaline salts. This excretion occurs chiefly in the urine, which becomes less acid, or even alkaline in reaction, and in the latter event contains bicarbonate of potash or soda. As a general rule, the urine soon regains its acidity, but when fairly large doses are given repeatedly, its action may be kept alkaline constantly. This is almost always accomplished in man by the administration of about 1015 G. (160-240 grs.) of sodium carbonate in 24 hours, but some persons require a still larger quantity, while others require much less. A tem- porary alkaline reaction lasting 2-3 hours may often be induced by a single dose of 2-3 G. The alkalies have the same effect on the excre- tion of the salts in the urine as the neutral salts large doses increase the sodium, potassium and chlorides of the urine. The injection of alkaline carbonates into the blood induces a more active secretion from the bronchial mucous membrane, according to Calvert, while Rossbach found it to have the opposite effect. It is questionable whether the alkali is excreted here. The blood of rabbits treated with alkalies is said to be more strongly ger- micidal than usual, and these animals show greater resistance to infection with anthrax bacilli. These effects are not due to the increased alkalinity HYDRATP:S AND CARBONATES OF THE ALKALIES. 545 of the blood directly, for serum is not rendered more bactericidal when alkali is added to it in test-tube experiments. When dilute alkaline solutions are applied to Isolated Organs, they gen- erally increase their activity for a time, but subsequently weaken it, while strong solutions are immediately poisonous. Thus the ciliary movement of epithelium is accelerated by dilute alkalies, the sodium salts acting more strongly than the potassium because of the poisonous K-ion of the latter. The heart also contracts longer and more strongly when it is perfused by a chloride of sodium solution rendered alkaline by carbonate of soda than when the solution is neutral. Somewhat stronger solutions increase its tonus and eventually cause systolic standstill. The arteries are con- tracted in the same way by contact with alkaline solutions, and are dilated when acids are perfused through them. Some of the secretions have also been found to be increased by the presence of alkalies, thus the glands of the frog's skin are stimulated by very dilute alkaline solutions. Loeb has recently observed that the presence of the OH ion causes frog's muscle to absorb considerable quantities of water from a dilute salt solution, while on the other hand Hamburger states that the addition of small quantities of alkalies to the drawn blood reduces the size of the blood cells. Zoethout states that some unicellular organisms prove much more resistant to the effects of the withdrawal of oxygen when they are placed in a slightly alka- line medium, and suggests as an explanation that the alkali antagonizes some poison formed during asphyxia. Strong alkaline solutions destroy all living tissues with which they come in contact. PREPARATIONS. POTASSII HYDROXIDUM (U. S. P. ), POTASSA CAUSTICA (B. P.), (KOH), potassium hydrate, caustic potash dry white pencils or fused masses, deliques- cent in the air and very caustic. Sodii Hydroxidum (U. S. P.) (NaOH), sodium hydrate or hydroxide, caustic soda white translucent pencils, deliquescent in the air, and very caustic. Liquor Potassii Hydroxidi (U. S. P.), Liquor Potasses (B. P.), solution of potassium hydrate, about 5 per cent., 0.6-2 c.c. (10-30 mins.), to be well diluted. Liquor Sodii Hydroxidi (U. S. P.), a solution of sodium hydrate in water, about 5 per cent., 1-4 c.c. (15-60 mins.), well diluted. Liquor Sodii Ethylatis (B. P.), an 18 per cent, solution of sodium ethylate (C 2 H 5 ONa) in absolute alcohol. It should be recently prepared, when it forms a colorless syrupy liquid, which decomposes in the presence -of water, and is very caustic. POTASSII CARBONAS (U. S. P., B. P.) (K 2 CO 3 ), a white granular powder of alkaline reaction, soluble in one part of water. 0.5-3 G. (5-30 grs.). SODII CARBON AS (B. P.) (Na 2 CO 3 + 10H 2 O), colorless crystals with an alka- line reaction and taste, soluble in about one part of water. 0.3-2 G. (5-30 grs.). Sodii Carbonas Exsiccatus (B. P.), sodium carbonate deprived of most of its water of crystallization, a loose, white powder resembling the ordinary carbonate in its reactions and solubility. 0.3-1 G. (5-15 grs.). Sodii Carbonas Monohydmtus (U. S. P.) (Na 2 CO 3 + H 2 O), a white crystalline powder without odor and strongly alkaline. Dose, 0.25 G. (4 grs.). POTASSII BICARBONAS (U. S. P., B. P.) (KHCO 3 ), colorless, transparent crystals with a saline, slightly alkaline taste and soluble in three parts of water. 0.5-2 G. (10-30 grs.). SODII BICARBONAS (U. S. P., B. P.) (NaHCO 3 ), a white, opaque powder, with a cool, alkaline taste, soluble in 11 parts of water at 15 C. 0.3-2 G. (5-30 grs.). Trochisci Sodii Bicarbonatis (U. S. P., B. P.). Sodium bicarbonate is contained in the Mistura Rhei et Sodse (U. S. P.). 35 546 INORGANIC SALTS, ACIDS AND BASES. Lithii Carbonas (U. S. P., B. P.) (Li 2 CO s ), a light, white powder with an alkaline taste, soluble in 80 parts of water, but more soluble in carbonic acid water. 0.2-0.6 G. (3-10 grs.). The preparations of magnesia and magnesium carbonate (see pp. 540-541) are prescribed more as antacids than as cathartics, and might be included in this list. Numerous alkaline mineral waters are used instead of the pharmacopoaial preparations, but as a general rule they contain only very small quantities of the carbonates, and perhaps act more through the large amount of water than through their alkaline reaction. Therapeutic Uses. The caustic alkalies are used Externally to a limited extent to remove growths such as warts from the skin. For this purpose the potash pencils are employed, but they are very de- liquescent and it is therefore difficult to limit their action to one spot, and to the superficial tissues. When the desired extent of cauteriza- tion has been obtained, the part should be washed with water, or with vinegar or some other dilute acid. The solution of sodium ethylate (B. P.) is said to be less painful than caustic potash. The carbonates are also used externally to some extent, chiefly in baths, which they render more irritant to the skin, and in which they tend to soften and remove the superficial horny layers of the epithelium more than ordi- nary water or solutions of the neutral salts. The carbonates are also applied in strong solution or as a paste in itching skin diseases, and often give relief. Internally the alkaline carbonates and more rarely the solutions of the hydrates are used for their effect on the stomach, and in cases of hyperacidity relieve the pain and eructation almost instantly. Even where no excessive acidity exists, the alkalies are often beneficial in small quantities, removing the distension and discomfort without apparently altering the digestion to any marked extent. The bicar- bonate of potash is more frequently used for this purpose than the others, and the solutions of the caustic alkalies are comparatively rarely employed. Whatever preparation be used, it ought to be well diluted to avoid the irritant action on the stomach wall. Instead of these alkalies the carbonate and oxide of magnesium may be employed in powder, and possesses the advantage of not causing any irritation and at the same time have some aperient action. In cases of hyperacidity the alkalies (antacids) are often given after meals, while when the secretion does not seem to contain an excessive amount of acid they are advised before meals, and may then be combined with other stomachics, such as bitters or volatile oils. The alkalies are also administered for their effects after absorption, and here the bicarbonate of potash is most frequently prescribed, while the hydrate solutions are rarely used. 1 Diabetes was formerly treated in this way, in the hope that the oxidation in the tissues would be increased, but there is little reason to suppose that the alkalies have any such effect on the metabolism, and it is now generally accepted that diabetes is not due to a general inability of the tissues to oxidize. 1 The acetates, citrates, etc., may also be used for this purpose (page 549). HYDRATES AND CARBONATES OF THE ALKALIES. 547 Experience too has shown that the glycosuria is not lessened appreci- ably by the use of the alkalies. When, however, diabetes induces an increased acid formation in the tissues, as is almost invariably the case in its later stages, the alkalies are of undoubted benefit in neutraliz- ing the oxybutyric acid formed and thus economizing the alkalies of the blood. In diabetic coma, temporary improvement may very often be attained by the use of large doses of alkalies. In gout, rheumatism, and the " uric acid diathesis " generally, the alkalies have been used very extensively, partly in the hope that the supposed increased combustion in the tissues would destroy a larger amount of the uric acid, and partly with the idea that the uric acid being neutralized in the tissues, would be excreted more easily and would have less tendency to be deposited. There are some grounds for believing that the alkaline carbonates are of benefit in gout and rheu- matism, but neither of these theories seems sufficient to explain their effects, for no increase in the oxidation has been shown to occur, and on the other hand the uric acid is not believed to exist in either the blood or the urine in such simple combinations as the urates. In the present position of the uric acid question and of the pathology of these diseases, however, it is futile to attempt to explain their thera- peutics, though it may be surmised that the alkalies may influence the formation of the uric acid rather than its excretion. The sodium and potassium salts have been used very largely, and the lithium carbonate has been advised on the ground that lithium urate is about four times as soluble as sodium urate. Lithium has also been administered in the form of the benzoate and salicylate in these diseases, in order to combine the solvent action of the base with the effects of these acids, but, as in so many other similar attempts, one of the chief factors in the action has been lost sight of; much too small quantities of the lithium compounds have been given to affect the reaction of the blood, and besides the salicylate and benzoate do not alter it at all, as they are neutral salts. These lithium compounds therefore seem to be superfluous in the treatment of these diseases. More benefit is derived from the treatment of gout and rheumatism by the alkaline mineral waters than by artificial preparations, and this is especially marked when patients are sent to the mineral springs. The alkalinity of most of the waters is very slight, and the conclusion is inevitable that the curative agency is not the alkalinity, but the large amount of fluid taken, together with the dietetic and other hygienic conditions. The alkaline preparations are also largely used for their effects in the urine. In cases of excessive acidity of the urine leading to pain and straining during micturition, the symptoms are relieved by these drugs rendering the fluid less irritating, and this relief is especially marked in irritable conditions of the bladder and urethra. They may also be of value in those cases by rendering the mucus more soluble in the bladder. In gravel the alkalies also give relief, and this has been attributed to their dissolving the uric acid in the urine, or rather to their keeping it in solution in the form of salts. In order to attain 548 INORGANIC SALTS, ACIDS AND BASES. this, the urine would have to be rendered alkaline, or at least neutral, and relief is given by quantities of the alkalies which are quite insuffi- cient to do this, so that it seems more probable that the effects are due to their increasing the amount of the urine, and thus rendering it more dilute than to their actually neutralizing the uric acid. Attempts have even been made to dissolve calculus in the bladder or in the kidney by treatment with the alkalies, but there is no question that this is hope- less. The solution of the alkalies formed in the urine is extremely dilute, and in fact, except under large doses, the reaction is not even constantly neutral. On the other hand, even the alkaline urates are by no means very soluble bodies, and are formed only with difficulty except in strong alkaline solutions. Again, alkaline urine is very liable to deposit phosphates in the bladder, and thus rather to increase the calculus than to diminish it. Experience has shown conclusively that the alkaline treatment does not remove calculus, although in one or two cases it is stated that soft calculi broke down into fragments under it, from the mucus which held the fragments together being dissolved. The pain and irritation of calculus may be relieved to some extent, however, from the acidity of the urine being lessened. The alkaline carbonates are also prescribed in cases of jaundice and gall-stone, often with benefit. This is not due to their acting on the bile directly in all probability, for it has been shown that they do not affect it in the normal animal ; the improvement may rather be ascribed to their lessening duodenal irritation. Sodium chloride solution is often injected intravenously in shock and heart failure, and it is found beneficial to add a small quantity of sodium bicarbonate (1 : 10,000) to it. Alkaline solutions should not be injected hypodermically, as sloughing has been observed repeatedly from this procedure. The bicarbonate of potash is often added to other expectorant reme- dies in the treatment of bronchial catarrh and bronchitis, and is be- lieved to increase the secretion and render it more fluid and more easily expectorated. The alkaline carbonates may be given as antidotes in poisoning with the corrosive acids, although magnesia is preferable, because it is less irritating to the stomach. In cases of Poisoning with the caustic alkalies, the treatment con- sists in the administration of dilute acids, of which the organic acetic, citric or tartaric are the best. The first is most readily obtained in the form of vinegar. No attempt should be made to pass the stomach tube, as it is liable to pass through the corroded wall of the oesophagus or stomach. General measures, such as central nervous stimulants, warmth, etc., may be taken. BIBLIOGRAPHY. Reichmann. Arch. f. Verdauungskrankheiten, i., p. 44. Kkigine. Arch, des Scienc. biologiques, iii., p. 461. Becker. Ibid., ii., p. 433. Glass. Arch. f. exp. Path. u. Pharm., xxx., p. 241. Salfcowskiu. Spilker. Virchow's Arch., cxvii., p. 570. HYDRATES AND CARBONATES OF THE ALKALIES. 549 Taniguti. Ibid., cxvii., p. 581. Horbaczewski. Monatsh. f. Chem., xii., p. 269. Freudberg. Virchow's Arch., cxxv., p. 566. Staddmann. Einfluss der Alkalien auf den menschlichen Stoffwechsel, 1890. Jawein. Ztschr. f. klin. Med., xxii., p. 43. Hegeler. Arch. f. Hyg., xl., p. 375. Culvert. Journ. of Phys., xx., p. 158. Passcdsky u. Cruszewit*ch. Maly's Jahresber., xxiii. (1893), p. 427. Harnack u. Kkine. Ztschr. f. BipL, xxxvii., p. 417. Zoethout. Amer. Journ. of Physiol., ii., p. 220. Garrey. Ibid., iii., p. 291. Piperazine and Quinic Acid. Several new organic compounds have been introduced of late years as solvents of uric acid in the tissues and urine. The best known of these is /-ITT OTT piperazine or diethylendiamine (NH<^pTT 2 p,TT 2 ^>NH) ; lycetol and lysidine are nearly related bodies. The latest remedy is quinic acid, C 7 H 12 O 6 , which is found in cinchona bark and in other plants ; its combinations with lithium citrate, urotropine and piperazine are known as urosin, chinotropine and sidonal. Piperazine and its allies dissolve uric acid readily in the test-tube, much more rapidly than lithium or borax, which are often prescribed for their solvent action; it was therefore hoped that these bases would prevent the deposit of uric acid in the body in gout by forming soluble urates, which would be eliminated in the urine. But very little of the piper?zine ingested reappears in the urine, and this quantity is too small to have any solvent action on the uric acid. And what does escape in this way is in combination with the stronger acids and not with the uric acid. When the kidneys are inflamed and necrosed in birds through the action of chromic acid, the uric acid, which would normally be excreted by the kidney, is deposited in various organs, but this does not occur except in the kidney if piperazine is administered. This has been used as an argument in support of the treatment of gout with piperazine, and some clinicians have had very favorable results from it, while others have been disappointed. It is said to relieve the discomfort due to the pas- sage of gravel in some cases, while failing in others, but it has not been shown to be of any value in the treatment of calculus, and the urine of patients treated with piperazine has no more solvent action on uric acid than normal urine. Piperazine seems to induce no symptoms in man or animals even when administered in large quantities. Quinic acid has been suggested as a treatment for gout on the theory that it would combine with glycocoll in the body and thus prevent the formation of uric acid, a theory based on most unsatisfactory grounds. As a matter of fact it has no effect whatever on the amount of uric acid excreted. In short there is every reason to believe that these new remedies will prove no more reliable than the older treatment of gout and the " uric acid diathesis." Piperazine is given in solution in doses of 1 G. (15 grs.). XV. THE ACETATE SERIES. As far as their immediate effects are concerned, the acetates of the fixed alkalies resemble the chlorides, owing any effect they possess to the salt- action. In the tissues however the acetates are oxidized and form car- bonates, so that the effects are those of the chloride before absorption, and those of the carbonate subsequently. They are probably partly decomposed by the hydrochloric acid in the stomach, and in the intestine they are rapidly absorbed. The oxidation seems to proceed rapidly, and is very complete, over 95 per cent, of the acetate disappearing, and only some 2-3 per cent, being excreted unchanged in the urine. The alkalinity of the blood and of 550 INORGANIC SALTS, ACIDS AND BASES. the urine is increased by the acetates as by the carbonates, and the amount of urine is increased. The oxidation of the acetates, of course, supplies energy to the body and they are therefore foods technically, but they are unable to replace the fats and carbohydrates, as they fail to lessen the nitrogenous tissue change (com- pare alcohol, p. 141). Practically they are useless as foods, as when given in sufficient amount they derange the stomach in the same way as common salt and also alter the character and amount of the urine. The acetates seem almost devoid of specific action they act only as salts by changing the physical properties of the body fluids or as alkalies after absorption. The other members of the acetate series have some action, how- ever, for the formate, propionate, butyrate and valerianate of soda have been shown to be very weak narcotics when they are injected hypodermically or intravenously ; this is especially marked in the case of the butyrate. Rather more of the formate escapes unchanged in the urine than of the acetate, while the others are apparently entirely oxidized. The butyrate differs from the acetate in being capable of taking the place of the carbohydrates and fats more completely, and in thus leading to an economy of the nitrogenous tissues of the body. All of the simpler salts of this series are equally rapidly absorbed from the intestine, but the cenanthylate and the caprylate resemble the saline cathartics in being very slowly absorbed. Probably this holds also for the higher members of the acetic acid series, including the salts formed by the decomposition of fats palmitates, stearates, etc. The Lactates resemble the acetates in being almost entirely inactive, but they are rather more slowly absorbed than the acetates. They are oxidized in the tissues for the most part, and resemble buty rates in limiting the nitro- genous waste, at any rate when they are given in moderate quantities. Lactic acid is also excreted in the urine, however, in considerable quantity. PREPARATIONS. Potassii Acetas (IT. S. P., B. P.), a crystalline salt of pleasant, saline taste and very soluble in water. 1-4 G. (15-60 grs.). Sodii Acetas (U. S. P.) resembles the potassium salt. Ammonii Aceias. (See page 553.) Strontii Lactas (U. S. P.), 1-2 G. (15-30 grs.). Acetate of potash has been largely used as a diuretic and in the treatment of gout and rheumatism. It acts here exactly as the alkaline carbonates and bicarbonates, but has the advantage of not neutralizing the gastric juice, or in any way affecting the digestion except from its salt-action, which may be minimized by exhibiting it in dilute solution. The citrates of the alkalies may be used for the same purpose, as they are not cathartic except in large quantities. (See Saline Cathartics, p. 536.) BIBLIOGRAPHY. Buchheim. Arch. f. phys. Heilk., 1857, p. 122. Mayer. Arch. f. exp. Path. u. Pharm., xxi., p. 119. Weiskeu. Flechsig. Centralbl. f. Phys., 1890, p. 36. Mattevre. Pfluger's Arch., xlix., p. 460. Pohl Arch. f. exp. Path. u. Pharm., xxxi., p. 289 ; xxxvii., p. 413. AMMONIA AND CARBONATE OF AMMONIA. 551 XVI. AMMONIA AND CARBONATE OF AMMONIA. Ammonia solution and carbonate of ammonia differ considerably from the corresponding hydrates or carbonates of the fixed alkalies in their effects. The gas evaporates rapidly from its watery solutions, and the carbonate gives off ammonia freely, so that the effects are very similar, although the solution of ammonia is much the more powerful. Owing to its volatility, ammonia penetrates more rap- idly and deeply than the fixed alkalies, and at the same time is less cor- rosive and less enduring in its effects. Applied to the skin in concen- trated solution, it may corrode to some extent, but ordinary dilute preparations act merely as rubefacients, like the volatile oils. Even concentrated solutions do not dissolve the epidermis like the fixed alkaline hydrates, but tend to penetrate through it and raise blisters. When inhaled, the irritation of the nasal mucous membrane causes a reflex stimulation of the vaso-motor centre, and consequent contrac- tion of the arterioles and augmented blood-pressure, while the respira- tion is first arrested, and then becomes deeper and fuller. The heart may be temporarily slowed by inhibitory reflexes. Three parts of ammonia in 10,000 of air cause sneezing, pain in the nose, and tears, when inspired by man, and 5 parts in 10,000 are dangerous when in- haled for some time (Lehmann). Ammonia is not absorbed by the lungs, and the syniptoms arise only from the local irritation and subse- quent inflammation. Concentrated solutions cause corrosion of the mouth, oesophagus and stomach similar to that seen in poisoning with the fixed alkalies, but some of the vapor, passing into the respiratory passages, often sets up spasm of the glottis, or such swelling of the mucous membrane of the larynx and trachea as to induce asphyxia. In cases of ammonia poisoning, therefore, the symptoms often arise, not so much from the gastric corrosion as from asphyxia, and death may occur very suddenly from this cause, The carbonate of ammonia,when swallowed, also causes slight gastric irritation, and in larger quantities nausea and vomiting. After absorption ammonia and its carbonate are rapidly changed to urea, and thus differ from the fixed alkalies in not rendering the blood more alkaline, and in having no effect on the urine except to increase the urea and thereby cause some diuresis. The carbonate of ammonia stimulates the central nervous system when it is injected into the blood in some quantity, but it is very doubtful whether either the hydrate or the carbonate has any such effect when absorbed from the stomach. (Cf. Ammonium Chloride, page 496.) PREPARATIONS. Aqua Ammonite Fortior (U. S. P.), a solution of ammonia in water, con- taining 28 per cent, of the gas by weight. Liquor Ammonite Fortis (B. P.), 32 per cent, by weight. Aqua Ammonite (U. S. P.), Liquor Ammonia (B. P.), an aqueous solution of ammonia of 10 per cent, strength by weight. 552 INORGANIC SALTS, ACIDS AND BASES. Spiritus Ammonice (U. S. P.), an alcoholic solution of ammonia containing 10 per cent, of the gas by weight. 1-2 c.c. (15-30 mins.). SPIRITUS AMMONITE AROMATICUS (U. S. P., B. P.), Aromatic Spirit of Hartshorn, Spirit of Sal Volatile, contains ammonia and ammonium carbonate along with several volatile oils dissolved in alcohol. 1-4 c.c. (15-60 mins.), in a glass of water. Linimentum Ammonias (U. S. P., B. P.), ammonia liniment, volatile lini- ment, contains about 3.5 per cent, of ammonia (2.5 per cent. B. P.). AMMONII CARBONAS (U. S. P., B. P.) is not the pure carbonate but a mix- ture of somewhat varying composition consisting of carbonate (NH 4 HCO 3 ) and carbamate of ammonia (NH 4 NH 2 CO 2 ). It releases ammonia in the air and has therefore its pungent taste and smell. It forms translucent, crys- talline masses, is very soluble in water and is contained in the aromatic spirit of ammonia. 0.2-0.6 G. (3-10 grs.) in dilute solution. Ammonia is contained in several of the tinctures of the B. P. (ammoniated tinctures) and in the Linimentum Camphorse Ammoniatum, etc. Therapeutic Uses. The aqueous solutions of ammonia are compara- tively rarely employed, although the strong solution has been advised as a vesicant in cases of renal disease, in which cantharides is contra- indicated. The ammonia solution has to be covered by a watch-glass in order to prevent its evaporation, and is said to be more painful than other vesicants. The liniment is used as a rubefacient in bruises and in other similar conditions. The gas arising from ammonium carbonate is often inhaled in cases of fainting or collapse, in order to elicit reflex stimulation of the medullary centres. The ordinary "smelling salts " used for this purpose consist of the carbonate reinforced with some of the strong solution and flavored with oil of lavender. The aromatic spirits of ammonia and the carbonate (in solution) are used as mild gastric stimulants in debility, flatulence and alcoholism, and are very efficient for a short time. Large doses of the carbonate (2 G.) have been used as emetics, and are less depressant than many others, such as tartar emetic or ipecacuanha. The carbonate of ammonia and the spirits or even the ordinary water of ammonia are .often given in cases of collapse or sudden heart failure. They are generally administered by the mouth and probably act here not directly on the heart and respiratory centre, as has been supposed, but reflexly from gastric irritation. They have also been in- jected subcutaneously or even intravenously for this purpose, and here the local action may be reinforced by a direct action on the medulla oblongata. The action lasts only a very short time, but is often suffi- cient to tide the patient over an acute collapse. In depression from many different causes the aromatic spirits of ammonia is a favorite remedy, and probably owes its value to its gastric action, and not to any changes in the central nervous system. The carbonate is often added to other expectorant remedies to render the bronchial mucous secretion more fluid. (See Ammonium Chloride, page 496.) Strong water of ammonia is applied locally in snake-bite, and is popularly believed to be very efficacious. It has no effect on the tox- albumins of snake poison, and probably is of little or no value in these cases. OXALATES. 553 BIBLIOGRAPHY. See Ammonium Chloride, page 496. Lehmann. Arch. f. Hygiene, v., p. 1. The Acetate of Ammonia acts in the same way as the chloride locally, but undergoes oxidation in the tissues, and the whole is changed to urea, so that the ammonia of the urine is not increased, but only the urea. In the form of its solution, the spirit of Mindererus, it is used as a diaphoretic and diuretic, and is often prescribed along with more powerful remedies in fever. PREPARATIONS. Liquor Ammonii Acetatis (U. S. P., B. P.), spirit of Mindererus, contains about 7 per cent, of the acetate with some free acetic acid and carbonic acid and must be freshly prepared. 10-25 c.c. (2-6 fl. drs.). Liquor Ammonii Citratis (B. P.) resembles the solution of the acetate. 2-6 fl. drs. XVII. OXALATES. The oxalates (NaOOC COONa, sodium oxalate) differ from the acetate series is not undergoing oxidation in the tissues, and in being poisonous to most forms of living matter. This poisonous action is shown in the frog by depression and final paralysis of the central nervous system, the brain being first affected, then the medulla oblongata and spinal cord. Later still, the terminations of the peripheral nerves and the muscles and heart are para- lyzed, twitching and fibrillary contractions of the voluntary muscles often being observed first. In mammals there is apparently at first a stimulation of the medullary centres, for rapid, deep breathing occurs in the rabbit, and vomiting and nausea in the dog, and according to some observers, the arterial tension is first increased through stimulation of the vaso-motor centre. Later the movements are wanting in coordination, the respiration becomes slow and dyspnoeic, the heart is weak, and the animal becomes comatose and dies, sometimes in convulsions. In cases of oxalate poisoning in man, the early symptoms are great mus- cular weakness, twitching of the muscles, especially of those of the face, more rarely convulsions ; later there follows collapse with a weak, fluttering pulse, pallor or cyanosis, coma and death. Oxalates are very poisonous to all forms of animal life and to plants con- taining chlorophyll, but are harmless to the moulds, bacteria and some alge. They are absorbed with great difficulty from the stomach and intestine, and cause irritation and effusion of liquid except in very dilute solutions. Added to the blood outside or inside the body, they prevent its coagulation, and the rennet ferment also fails to coagulate milk in the presence of small quanti- ties of oxalate (see Calcium). The frog's heart is very much weakened by the addition of oxalate of soda to the blood perfused through it, while the mammalian heart is not affected by very small quantities, but if the injection of oxalate be continued, becomes suddenly weaker. The action on the cen- tral nervous system has been mentioned already, and consists in depression, which is sometimes intermixed with, or preceded by symptoms of stimulation. When the ordinary nerve-muscle preparation is soaked in oxalate solution, the same twitching and tremor of the muscle is observed as when the salt is injected into the frog. Later the nerve ends are paralyzed, and the nerve 554 INORGANIC SALTS, ACIDS AND BASES. fibres lose their irritability, as is indicated by the disappearance of the elec- trical current of action. The muscle is extremely weak, and according to several observers, loses its irritability, while Locke finds that it can be made to contract locally by strong currents, even after being soaked for several hours. The post-mortem rigor does not seem to be prevented by oxalate as has been stated by some observers. Oxalate solutions precipitate lime salts, and as it is well known that lime is an essential constituent of living matter, it has been suggested that the oxalates cause these changes in the organism not through any direct action on protoplasm, but through their precipitating the calcium and thus chang- ing its ordinary relation to the proteids. This explanation has been sup- ported by the discovery that calcium salts added after oxalates restore the lost function in many cases, although this of course admits of the explana- tion that the calcium merely throws the oxalate out of solution, and does not really supply fresh lime to the tissues. The presumption is strong however that the action of the oxalates is due, at any rate in part, to their precipi- tating the calcium in the tissues, although they may have a specific action on living matter in addition. The alkalinity of the blood was found to be much reduced by the admin- istration of neutral oxalates (Meyer), and it has been surmised that this is because the oxidation of the tissues is retarded by the presence of oxalates in the blood. This may account for the appearance of a reducing body in the urine of animals poisoned with oxalate ; it sometimes occurs in poisoning in man and is said not to be dextrose. Practically the whole of the oxalate ingested is excreted in the urine in the form of oxalate of calcium, and the insoluble crystals are often deposited along the urinary tubules and may stop them up entirely and thus cause anuria, congestion and inflammation of the kidney ; albuminuria is often the most marked symptom in slight poisoning in man. The deposits of oxalates often form white lines running from the base to the apex of the renal pyra- mids, w r hich are quite evident macroscopically at the autopsy. Small oxa- late calculi have also been produced in the pelvis of the kidney, bladder, or ureter through the prolonged administration of oxalate or oxamide to animals. Not infrequently these renal changes are the only lesioos found post-mortem in cases of poisoning with oxalates. The prolonged administration of oxalates to animals has been found to induce changes in the skeleton, for sheep fed on plants containing much ox- alate, are found to have less lime in the bones than usual, and in rabbits symptoms of rickets are said to be induced from the lessened absorption of lime. The other members of the oxalate series, malonates (CH 2 (COONa) 2 ) and succinates ((CH 2 ) 2 (COONa) 2 ), differ from the oxalates in being very much less poisonous, the fatal dose of malonate of soda being about twenty times that of the oxalate, and the succinate being almost indifferent. The malo- nate is almost completely oxidized in the tissues, and succinate disappears completely. It is significant that malonic and succinic acids form much more soluble salts with lime than does oxalic acid. Both malonate and suc- cinate of soda are absorbed only slowly from the intestine, and act as saline cathartics. The oxalates are not used in therapeutics. In cases of oxalate poisoning the natural antidote is lime, which forms an insoluble precipitate in the stomach and may also relieve the symptoms induced by the withdrawal of lime from its normal combination in the tissues. At the same time large quantities of water and diuretics may be given in order to wash out the crystals of oxalate from the urinary tubules. ACIDS. 555 BIBLIOGRAPHY. (See Calcium.) Krohl Arb. a. d. pharm. Inst. zu Dorpat, vii., p. 130. Meyer. Arch. f. exp. Path. u. Pharm., xvii., p. 304. Neubercjer. Ibid., xxvii., p. 39. Oaglw. Ibid., xxii., p. 246. Pohl Ibid., xxxvii., p. 413. Ebstein u. Nicolaier. Virchow's Arch., cxlviii., p. 366. Ringer. Practitioner, xxxiv., 1885, p. 81. Locke. Journ. of Phys., xv., p. 119 ; xvii., p. 293. Hawaii. Ibid., xvi., p. 476. Heymanns. Arch. f. Anat. u. Phys., 1889, p. 168. Marfori. Arch. Ital. de Biol., xxvi., p. 194. Nathusius. Centralbl. f. Phys., 1897-98, p. 608. Vietinghoff-Scheel. Arch, internat. de pharmacodyn. , viii., p. 225. XVIII. ACIDS. Some acids owe their activity in the organism almost entirely to their acidity, i. e., to the hydrogen ion, which is much more powerful than the potassium ion, but otherwise stands on the same plane with it ; those acids may therefore be treated of together. In the case of many other acids such as prussic or salicylic acid, the effects of the acidity or hydrogen ion are insignificant in comparison with those of the rest of the molecule or the negative ion, and these are treated along with their salts. Action. The acids owe their action on living tissues to their neu- tralizing alkalies, to their withdrawing water, when in concentrated form, and to their precipitating some of the proteids, more especially the globulins. Most living matter is neutral Or slightly alkaline in reaction, and seems to be incapable of existing in acid media. Exceptions are met with in some of the moulds and in other vegetable organisms which live in somewhat acid solutions, but even these are destroyed by more concentrated solutions, perhaps because the acids precipitate their pro- teids. Acids are therefore Protoplasm Poisons and antiseptics of some power. Hydrochloric acid is found to delay the growth of organisms, and even to destroy the great majority of the less resistant forma *n 0.2-0.3 per cent, solution, or in the percentage in which it exists in the gastric juice. The others vary in strength largely according to their acidity, that is, according to the number of hydrogen ions, or the amount of dissociation. The anion has also some effect in many cases. When sulphuric or nitric acid is applied to the Skin in concentrated form, it acts as a powerful caustic, destroying the epidermis and pene- trating to some distance into the skin and subcutaneous tissues, in which it causes necrosis. This is of course accompanied by great pain, and if much of the skin is attacked, by shock and collapse and symptoms similar to those seen in severe burns. Sulphuric acid causes a white, later a brown or black eschar, nitric acid a yellow. Hydro- chloric acid is less liable to cause wholesale destruction of the skin, but penetrates the epidermis and raises blisters. The organic acids 556 INORGANIC SALTS, ACIDS AND BASES. and phosphoric acid are still less irritant, but cause redness and even blistering when applied in concentrated solution. Dilute solutions of the acids may act as slight irritants to the skin, and often cause a feel- ing of stiffness and numbness, perhaps from precipitating the proteids. The corrosive action of the acids is much more marked when they are applied to the less resistant Mucous Membranes. Even small quan- tities of strong sulphuric acid striking the eye are sufficient to destroy the sight. In the Mouth, (Esophagus, and Stomach the corrosive action is evi- denced by complete destruction of the mucous membranes which come in contact with the strong acid. The oesophagus and stomach may be perforated, and this, along with the shock and collapse, often proves immediately fatal, or if the patient recovers temporarily, the erosions may give rise to cicatricial contractions and death from inanition. Hydrochloric acid and the stronger organic acids are capable of caus- ing corrosion of the mucous membranes, but this is not so extensive generally as that following nitric and sulphuric acid. The corrosion from acids differs from that from alkalies, in the tissues being shrunken, hard and brittle, while after a caustic alkali they are soft and swollen and have a slimy soapy appearance. The symptoms of corrosive acid poisoning are intense pain in the mouth, throat and stomach, vomiting and often diarrhoea, shock and collapse, with rapid, weak pulse and shallow respiration. The tem- perature is often subnormal, and death occurs in the course of a few hours. When fuming acids are swallowed, and especially in poisoning with hydrochloric acid, the irritant vapor passing into the respiratory passages may cause spasm of the glottis, or oedema of the larynx, and prove immediately fatal from asphyxia. Even one part of hydro- chloric acid vapor in 20,000 of air causes sneezing and pain in the throat and chest (Lehmann). Dilute solutions of the acids have a characteristic taste, and induce a reflex flow of saliva and an astringent feeling in the mouth and throat from their causing a coagulation of the superficial layers of proteids. In the stomach they displace any weaker acids from their combinations with bases, and may have some antiseptic action. The gastric juice is normally acid, containing about 0.2 per cent, of free hydrochloric acid, and this acid reaction is essential to the action of pepsin. Other acids may replace the hydrochloric acid in digestion, and a good deal of work has been done in determining the relative value of the acids for this purpose. This is done by adding different acids to solutions of pepsin in test-tubes, and noting the amount of fibrin or other proteid which is digested in the course of a number of hours. These experi- ments have shown that hydrochloric is better than most other acids, but is perhaps surpassed by hydrofluoric and oxalic acids ; but the re- sults seem to vary with the particular pepsin used, that obtained from the dog and calf differing somewhat in its relations to acids from that of the child. Their poisonous action precludes the use of either flu- oric or oxalic acid in the stomach, and the other acids seem inferior to ACIDS. 557 hydrochloric acid, so that both clinical experience and experiment point to the last as the most suitable acid for use in the stomach. The acids are absorbed from the alimentary canal fairly rapidly in most cases. In the Blood and Tissues they do not exist as acids but as salts, for the reaction of the blood must remain slightly alkaline throughout life, and if sufficient acid be given to neutralize the alka- lies of the body, the animal dies before the blood becomes neutral, al- though after death it may be found to be acid. The means provided by the economy to neutralize acids differ in different animals ; in the herbivora the fixed alkalies of the blood and tissues are called upon chiefly, and if more acid be absorbed than can be neutralized by these, the animal dies ; in the carnivorous animals and in man, a further pro- tective mechanism exists, for in these ammonia is liberated by the tis- sues, and serves to neutralize the acid, and thus saves the fixed alka- lies. The difference is relative and not absolute, however, for the herbivora also develop some ammonia, and the carnivora employ some of the fixed alkalies to preserve the normal reaction of the tissues. Man appears to stand midway between the two classes, for while am- monia appears in the urine after acid absorption, the fixed alkalies are also present in excess. Much larger amounts of dilute acids may therefore be absorbed without serious symptoms by man and by the carnivora than by the herbivora. The explanation of this difference between the flesh-eating and the plant-eating animals is to be found in the nature of their food. The flesh-eaters are accustomed to the for- mation of some acid in their tissues, because the alkalies of their food are insufficient to neutralize the acids formed by the oxidation of the organic matter, and they would gradually be deprived of all their al- kaline salts, therefore, were they not protected by the formation of ammonia. On the other hand, the herbivorous animals absorb much larger quantities of the organic salts of the alkalies in their food, and these forming carbonates in the body, serve to neutralize what acid is formed in the tissues. In ordinary circumstances, therefore, they have no need to protect the fixed alkalies, and are unprovided with any mechanism for this purpose. When an excess of acid is absorbed, they neutralize it by means of the fixed alkali of the tissues and blood, and this leads to a lessened alkalinity of the blood, which becomes unable to carry so much carbonic acid from the tissues to the lungs. Thus in acid poisoning in rabbits, the alkalinity of the blood has been found to be so greatly reduced that instead of containing some 25 vol- umes of carbonic acid per cent, of blood, it carried only two volumes per cent, or very little more than could be dissolved in the same amount of water. When this occurs, the tissues are unable to rid themselves of their carbonic acid, 1 and a series of symptoms follow, commencing in deep, labored, rapid, afterwards shallow respiration ; the heart is weak, a condition of collapse follows, and eventually the 1 This is the explanation universally adopted, but Loewy and Munzer have recently shown that some additional factor is involved in the action of acids on herbivora. Spiro states that in some cases the acid is excreted in the urine with greater difficulty in the herbivora than in the carnivora. 558 INORGANIC SALTS, ACIDS AND BASES. respiration ceases, the heart continuing to beat for some time longer. The quantity required to poison a rabbit in this way is about 1 G. of hydrochloric acid for each kilogm. body weight. The injection of sodium carbonate, even in the last stage of intoxication, is followed by rapid recovery, from more alkali being supplied the blood and tissues, while other carbonates are not so useful owing to the action of the basic ion. The blood-pressure in rabbits is much reduced by the acids, from depression of the vaso-motor centre and the heart. In carnivora and man, the absorption of dilute acids does not alter the alkalinity of the blood to any marked degree, and no serious symptoms arise from this cause. The salts formed in the blood and tissues after the absorption of acids are rapidly Excreted by the kidneys, which however retain as much alkali as possible in the body and thus excrete the salts in an acid form. Hence there arises in some cases irritation of the kidneys, with albumin, and even blood, in the urine, which is rendered more acid than usual and causes a sensation of heat and smarting in the bladder and urethra. In the herbivora the reaction changes from alkaline to strongly acid, and large quantities of the salts of the alkalies appear, while in the carnivora some increase in the sodium and potassium of the urine occurs along with a much greater increase in the ammonia. The total nitrogen is somewhat increased from the large amount of ammonia, but the urea is slightly decreased. Some authors have found an augmented excretion of lime in the urine, while others state that it is less than usual. Not infrequently fatty degeneration of the heart, liver, muscles or kidney has been observed in corrosive acid poisoning, when the patient survived for a few days, and Fraenkel and Reiche found a form of necrosis of the renal cells in these cases. These changes are not due to free acid in the blood, but their exact cause has not been satisfactorily determined. The prolonged treatment of animals with acids has been found to be fol- lowed by anaemia and loss of flesh and strength, which are probably attri- butable to the disturbance of the digestion and not to any specific action of the acids. Acids applied directly to the living tissues lessen their vitality, and un- less there is sufficient alkali present to neutralize them, soon destroy it entirely. In some cases they tend to cause a temporary increase in activity at first ; thus the cilia of ciliated epithelium have been found to move more rapidly at first in very dilute acids and then to cease all movement, while muscle seems to be rendered weaker and less irritable at once. As in the case of alkalies, Loeb finds that dilute acid causes muscle to imbibe more water than salt solution does, and Hamburger finds that the red blood cells are increased in size by the addition of small quantities of acid to the blood out- side the body. The frog's heart is weakened and dilated by the addition of acid to a perfusing solution, and the muscular wall of the vessels also re- laxes. The addition of acids to the blood tends to agglutinate the red cells and to form methsemoglobin. Therapeutic Uses. The acids are used in medicine only to a limited extent, and some of the official preparations might well be dispensed with. ACIDS. 559 They may be employed to give flavor to draughts in fever and in the thirst of diabetes, the most popular forms being those formed from fruits, such as lemons, limes, or grapes. The taste is due to the sugars, acids, and volatile oils of the fruits, and is modified by the presence of inert colloid substances, such as the pectins. The acids, of which citric, tartaric and malic are the chief, are very important factors in the effect, for if these be neutralized, the fruit juices become insipid, and do not quench thirst so thoroughly. The so- called grape cure, in which very large qualities of grapes are eaten, owes most of its value to the large amount of water taken, although the acids and salts may act as aperients in the same way as the saline cathartics. Instead of the fruit juices, carbonic acid waters may be advised, and occasionally other acids, such as phosphoric or sulphuric, are prescribed to give flavor. Acids are also used in certain forms of dyspepsia in which the hy- drochloric acid of the stomach is deficient. Hydrochloric acid is most frequently prescribed for this purpose, although nitric and nitrohydro- chloric acids have also some reputation ; the hydrochloric acid is certainly more efficient than these in test-tube experiments on di- gestion. The forms of dyspepsia thus treated are generally those aris- ing from a sedentary life or in the course of convalescence, and the acids are often prescribed along with the bitter stomachics and are to be taken about half an hour before meals. Irritation of the stomach, or hyperacidity of the gastric juice is of course a contraindication. In cases of alkaline poisoning, the acids are the natural treatment ; the organic acids should be preferred for this purpose, as they are less liable to cause additional corrosion, and acetic acid in the form of vine- gar is more likely to be at hand than any other. In every case in which acids are prescribed internally, they have to be given largely diluted, as otherwise they irritate the throat and stomach. They are taken through a glass tube, in order to prevent ^ as far as possible their action on the teeth. Strong acids have some effect in arresting hemorrhage (styptics) when applied directly to the bleeding point, but are much inferior to some of the metallic salts, such as the iron perchloride. Externally, the acids are used to some extent as corrosives, strong nitric acid being not infrequently used to destroy small tumors, to cauterize the os uteri and for similar objects. Its action is more easily localized than that of potash and on the other hand is more powerful than the metallic salts such as silver nitrate and zinc chloride. In dilute solution, they are sometimes applied to the skin to lessen ex- cessive local sweating and diluted vinegar is often used to sponge fever patients. In cases of corrosive Poisoning with acids, the first indication is to neutralize the acids as far as possible by giving alkalies. These ought not to be in themselves corrosive, arid the best antidote is therefore the insoluble magnesia and magnesium carbonate. Lacking these, the most readily accessible alkali is the best, and the lime may be scraped from walls or ceiling, or chalk, soap, or wood ashes may be given. The walls of the stomach and oesophagus may also be pro- tected by giving milk or white of egg, or the acid may be rendered less corrosive by diluting it with large quantities of water. 560 INORGANIC SALTS, ACIDS AND BASES. BIBLIOGRAPHY. Walter. Arch, f. exp. Path. u. Pharm., vii., p. 148. Salkowski. Virchow's Arch., Iviii., p. 1. Jacquet. Arch. f. exp. Path. u. Pharm., xxx., p. 311. Hahn. Virchow's Arch., cxxxvii., p. 597. Jaworski. Deutsch med. Woch., 1887, Nos. 36-38. Hiibner. Fortschritte der Med., xii., p. 163. Fraenkelu. Reiche. Virchow's Arch., cxxxi., p. 130. Wroblewski. Zeitschr. f. phys. Chem., xxi., p. 1. Runge. Arch. f. exp. Path. u. Pharm., x., p. 324. Freudberg. Virchow's Arch., cxxv., p. 566. Dunlop. Journ. of Phys., xx., p. 82. Loeb. Pfltiger's Arch., Ixix., p. 1 ; Ixxiii., p. 422. Winterberg. Ztschr. f. phys. Chem., xxv., p. 202. Limbeck. Ztschr. f. klin. Med., xxxiv., p. 419. Loewyu. Munzer. Arch. f. [Anat. u.] Phys., 1901, p. 81. Spiro. Beitrage z. phys. und path. Chemie, i., p. 269. Compare Alkaline Hydrates and Carbonates, page 547. For the specific effects of the anions of the acids, see chlorides, phosphates, acetate^, oxalates, etc. Sulphuric Acid. Sulphuric acid is one of the most corrosive acids when it is applied in concentrated form, and often induces complete charring of the tissues, and a coal-black slough. Acidum Sulphuricum (U. S. P., B. P.), concentrated sulphuric acid, con- taining at least 92.5 per cent, by weight of absolute sulphuric acid U. S. P., containing 98 per cent. B. P. Acidum Sulphuricum Dilutum (U. S. P., B. P.) contains 10 per cent. U. S. P., 13.65 per cent. B. P. of absolute sulphuric acid. 0.6-2 c.c. (10-30 mins.). Acidum Sulphuricum Aromaticum (U. S. P., B. P.) is an alcoholic solution flavored with ginger and cinnamon. The IT. S. P. preparation contains 20 per cent., the B. P. preparation 13.8 per cent, of sulphuric acid. 0.3-1 c.c. (5-15 mins.) in a glass of water. Sulphuric acid and its preparations are not largely used. It is occasionally applied as a caustic, but nitric acid is generally preferred. Internally it is largely used as a prophylactic and remedy in lead poisoning, but it is prob- ably of little value here. (See Lead.) It has also been advised in a number of conditions, such as diarrhoea, cholera, night sweats, but has not proved efficacious in any of them. When prescribed internally the aromatic acid is the best form, but sulphuric acid could be dispensed with entirely in thera- peutics. Nitric Acid. Nitric acid is equal or superior to sulphuric in its corrosive action. It stains the skin and tissues a bright yellow or yellowish-brown, and this serves to dis- tinguish cases of poisoning under the two acids. Acidum Nitricum (U. S. P., B. P.) contains 68 per cent, of absolute nitric acid (HNO 3 ) (B. P. 70 per cent.). Acidum Nitricum Dilutum (U. S. P., B. P.) contains 10 per cent. U. S. P., 17.44 per cent. B. P. by weight of absolute nitric acid. 0.6-2 c.c. (10-30 mins.). A glass rod dipped in concentrated nitric acid is used as a corrosive. The dilute acid has been advised in dyspepsia, but is generally considered in- ferior to hydrochloric acid, and has been shown to be much less efficient in artificial digestion. It has also some reputation in certain liver diseases, but is supposed to be inferior to the nitrohydrochloric acid. Nitric acid is occasionally used in some intestinal conditions accompanied by diarrhoea. ACIDS. 561 Hydrochloric Acid. Hydrochloric acid is less corrosive than the two preceding acids, and tends to cause blistering on the skin rather than necrosis. It may cause actual loss of substance, however, when applied to the mucous membranes in concentrated form, and stains the mouth a whitish color. Acidum Hydrochloricum (U. S. P., B. P.), muriatic or hydrochloric acid, contains 31.9 per cent, by weight of the gas HC1. (B. P. 31.79 per cent.) Acidum Hydrochloricum Dilutum (U. S. P., B. P.) contains 10 per cent. (B. P. 10.58 per cent.) of hydrochloric acid gas. 0.3-2 c.c. (5-30 mins.) in a glass of water. Concentrated hydrochloric acid is scarcely used in therapeutics. The diluted acid is often prescribed in dyspepsia in which there seems to be a deficiency of the natural acid secretion. In cases of diarrhoea in which excessive putrefaction of the intestinal contents is present, it may be of benefit when prescribed along with other drugs ; this action is probably explained by its disinfecting the stomach contents, as the hydrochloric acid of the gastric secretion normally does ; for the double sulphates of the urine certainly diminish under its use in many cases. It is said that hydrochloric acid prevents the lactic fermentation in 1 : 1,000 dilution, and that in addi- tion to its action on the digestive ferment it increases the peristalsis of the stomach. BIBLIOGRAPHY. Cohn. Zts. f. phys. Chem., xiv., p. 74. Hirschfeld. Pfliiger's Arch., xlvii., p. 510. Kast. Maly's Jahresbericht, 1889, xix., p. 271. Schuele. Ztschr. f. klin. Med., xxix., p. 67. Lehmann. Arch. f. Hygiene, v., p. 1. Nitrohydrochloric Acid. Nitrohydrochloric acid is formed by mixing hydrochloric and nitric acid, and contains not only the original acids, but a number of decomposition products, such as chlorine, nitroxychloride (NOC1) and nitrous acid. The strong acid (aqua regia) is the most powerful solvent and oxidizing agent known, dissolving such refractory metals as platinum and gold. Acidum Nitrohydrochloricum (U. S. P.), nitromuriatic acid, aqua regia, is formed by mixing 180 parts of nitric acid with 820 parts of hydrochloric acid. Acidum Nitrohydrochloricum Dilutum (U. S. P.) is formed by mixing 40 c.c. of nitric acid with 180 of hydrochloric and diluting the whole to one litre. 0.5-1 c.c. (5-15 mins.). Acidum Nitrohydrochloricum Dilutum (B. P.) is formed by mixing 6 parts of nitric acid and 8 parts of hydrochloric acid with 50 of distilled water. 5-20 mins. The diluted acid alone is used in therapeutics, and does not seem so efficient in ordinary dyspepsia as the dilute hydrochloric acid, but has some reputation in the treatment of liver diseases and jaundice, though no explanation of its action in these conditions has been offered. The acids cannot act as such except in the alimentary canal, but in the nitrohydrochloric acid other con- stituents, such as chlorine, are present, and it is conceivable that some of these may have a specific effect on the liver ; further proof would seem to be required, however, that the treatment is really of value. The acid is ordinarily given by the mouth, but some authorities advise that it be applied in the form of a foot-bath or of an ordinary bath, and others apply it in a compress over the liver. These external applications are stated to be even more efficacious in hepatitis than the internal administration, and this serves only to strengthen the doubt of the value of the remedy, for it is contrary to all experience that such bodies should be absorbed in any quantity from the skin, and their local action as cutaneous irritants does not differ from that of other drugs. 36 562 INORGANIC SALTS, ACIDS AND BASES. Phosphoric Acid. Phosphoric acid is much less corrosive and irritant than the other miners acids, but in large, concentrated doses may cause gastro-enteritis. Acidum Phosphoricum (U. S. P.) contains 85 per cent., Acidum Phosphor cum Concentratum (B. P.), 66.3 per cent, of absolute phosphoric acid (H 3 PO 4 Acidum Phosphoricum Dilulum (U. S. P., B. P.) contains 10 per cent.,' U. P., and 13.8 per cent., B. P., of phosphoric acid. 0.3-1.3 c.c. (5-20 mins. Phosphoric acid has been used to some extent to form cooling draughts i fever. It has also been prescribed in various cachectic conditions on tt theory that these were due to a deficiency of phosphates in the food an tissues ; but it has never been shown to be of any benefit, and experimem have proved that the animal tissues are unable to build up phosphori compounds from the inorganic phosphates. Sulphurous Acid. Sulphurous acid differs from the preceding members of the group i its powerful reducing action, through which it becomes oxidized to sul phuric acid, and which renders it strongly poisonous to protoplasm i general, quite apart from its acidity. Sulphurous acid anhydride : accordingly used to a considerable extent to disinfect rooms and furn ture after infectious diseases ; for this purpose sulphur is burned in It room, which ought to be rendered as air-tight as possible, and tli fumes are allowed to act for several hours before the room is ventilatec The value of this method of disinfection has been called in questioi but there is no doubt that sulphurous acid gas is fairly germicidal whe it is applied along with moisture. It* is not capable of such a wide aj plication as formaline, because sulphurous acid bleaches many colorin matters, and the procedure is open to the objection that it may lend sense of security which is quite unwarranted, and may lead to the neg lect of other measures. The disinfection to be of any value must b thoroughly carried out, and can only be applied to inanimate objects, a the fumes are fatal to the higher animals, even when much less conceu trated than are necessary to destroy bacteria. In order to be of service at least one volume of SO 2 ought to be present in each hundred volume of air, and even this concentration is insufficient to destroy the spores c bacteria. Novy * recommends 3-6 pounds of sulphur to be burned fo each 1,000 cubic feet of space; the walls and floor should be sprayed wit] water, and the room must be kept perfectly closed for at least 20 hours The chief symptoms of poisoning with sulphurous acid are those o irritation of the mucous membranes, and if the solution be swallowe< these may not differ from those of the other acids. Sulphurous aci< penetrates the tissues more rapidly than most of the others owing t< its gaseous form, and does not cause actual loss of substance as sul phuric acid does. In poisoning from the inhalation of the anhydride on the other hand the symptoms arise chiefly from the respiratory tract. Even in five part in 10,000 it acts as an irritant, causing sneezing, coughing and lachry mation, and in somewhat greater concentration it becomes entirely ir respirable ; still smaller quantities in the air cause bronchial irritatioi 1 Novy and Waite. Medical News, Ixxii., p. 641. ACIDS. 563 and catarrh, when inhaled for some time. Sulphurous acid is neu- tralized and oxidized for the most part to sulphates in the tissues, or probably partly in the course of absorption. The solution of sulphurous acid of the pharmacopoeia is used to a limited extent as an antiseptic solution in skin diseases. It is more irritant to the broken skin than many other equally powerful antiseptics. Acidum Sulphurosum, U. S. P. A solution of not less than 6.4 per cent. by weight of sulphurous acid gas (SO 2 ) in water. B. P., a solution contain- ing 6.4 per cent, of hydrogen sulphite (H 2 SO 3 ) corresponding to 5 per cent, by weight of sulphurous anhydride (SO 2 ). Hydrofluoric Acid is strongly corrosive and prevents the growth of bac- teria in solutions of one per mille. After absorption it induces the specific fluoride action (see page 525). Organic Acids of the Fatty Series. The organic acids have a much less marked local action than the inor- ganic, causing little or no corrosion unless when applied to mucous surfaces in very concentrated form. They are absorbed as salts of the alkalies, but do not as a general rule reduce the alkalinity of the blood or render the urine more acid, because they are oxidized to carbonates in the tissues. Ox- alic acid is the chief exception to this rule, but the specific action of the ox- alates is powerful enough to conceal the acid action to a great extent. Acetic Acid applied in concentrated solution to the skin causes irritation and congestion and eventually blistering, but does not induce necrosis ex- cept of the most superficial layers. The congestion is often followed by marked pallor instead of by blistering ; and this has been explained by con- traction of the vessels, but may be due to a precipitation of the proteids of the skin. In the mouth and stomach it acts as an irritant, causing vomiting, great pain, collapse and even death ; the epithelium is found thickened and occasionally contains haemorrhages. Dilute acetic acid (vinegar) has little effect apart from its acid taste, and is used largely as a flavoring agent and condiment. The prolonged use of large quantities may however give rise to gastric irritation and to loss of appetite and weight. Acidum Aceticum Glaciale (U. S. P., B. P.) (HC 2 H 3 O 2 ) is almost absolute acetic acid (99 per cent.), and becomes crystalline at a temperature some- what below 15 C. (60 F.). Acidum Aceticum (U. S. P., B. P.) contains 36 per cent, of absolute acetic acid U. S. P., 33 per cent. B. P. Acidum Aceticum Dilutum contains 6 per cent, of absolute acetic acid U. S. P., 4.27 per cent. B. P. (Dilute acetic acid is used to form the official aceta except the Acetum Cantharidis, B. P.) 2-8 c.c. (-2 fl. drs.). Acetic acid is sometimes applied to the skin as a slight local irritant in contusions, and in very dilute solutions to cool the surface and to prevent excessive local perspiration. It has been used as a styptic in slight haemor- rhage, and may be inhaled for this purpose in epistaxis. Vinegar is also inhaled in cases of fainting, in order to induce a reflex stimulation of the vaso-motor centre through irritation of the nostrils. In cases of poisoning with alkalies vinegar is often the most convenient acid and in addition is less likely to do harm than the inorganic acids. Acetic acid itself is not used as a corrosive, but one of its derivatives, tri- chloracetic acid (CC1 3 COOH), has been employed with good results. Formic Acid resembles acetic acid in most points, except that it is more volatile and more irritant, that less of it is oxidized in the tissues, and that given in large quantities it is said to induce nephritis. It is not used in therapeutics. The other acids of the acetic acid series resemble acetic acid in their ef~ 564 INORGANIC SALTS, ACIDS AND BASES. fects, but become less irritant as they become more complex and less easily dig sociated. Lactic Acid resembles acetic acid in its behavior in the organism (se page 550). It was suggested at one time that sleep following muscular ex ertion was due to the lactic acid formed in the muscles, and this acid wa therefore recommended as a hypnotic, but has been shown to be of no valu for this purpose. Kickets, rheumatism and other diseases were also at on time attributed to the excessive formation of lactic acid in the tissues, bu this theory is only of historical interest. Under the impression that lacti acid was the normal acid of the gastric digestion, it was at one time used ii dyspepsia. Acidum Lacticum (U. S. P., B. P.) is obtained by the fermentation of mill sugar or grape sugar, and contains 75 per cent, of absolute lactic aci< (HCj^Og). It is a colorless liquid of strong acic 1 taste. Lactic acid has been used recently as a caustic application to malignan ulcers and diphtheritic membranes. Oxalic Acid is frequently used as a poison by suicides, either as such or a the acid potassium salt (salt of sorrel or essential salt of lemons). Poisoning has repeatedly occurred from oxalic acid having been mistaken for magnesiun sulphate, which it resembles in appearance. The symptoms are those of aci< poisoning, along with the specific effects of the oxalates (see page 553) Oxalic acid is not used in therapeutics, although it has been said to be bene ficial in amenorrhcea. Tartaric Acid induces symptoms of gastric irritation when taken in larg doses, and has been the cause of fatal poisoning in a few cases. It is slowl; absorbed, and some of it escapes combustion in the tissues and is excreted ii the urine in the form of the acid tartrate. (See Tartrates, page 535.) Acidum Tartaricum (IT. S. P., B. P.) (H 2 C 4 H 4 O 6 ), colorless crystals ver soluble in water. 0.3-1.3 G. (5-20 grs.). Tartaric acid is prescribed with the carbonates and bicarbonates to forn effervescent draughts ; the tartaric acid ought to be slightly in excess in or der to lend its pleasant acid taste, the usual proportion being about eigh parts of acid to seven parts of sodium bicarbonate. These effervescent mh tures formed with the tartrates act as saline cathartics in large doses (st page 537). Tartaric acid may be prescribed in dilute solution with sug and a drop of volatile oil as a lemonade, which is cheaper than that forme with citric acid. Citric Acid resembles tartaric acid in its action, but appears less irritan and no case of serious poisoning is recorded from its use. It is slowly al sorbed like tartaric, but seems to be almost entirely oxidized in the tissue: Acidum Citricum (U. S. P., B. P.) (H 3 C 6 H.O 7 + H 2 O) resembles tartaric aci in its properties for the most part. 0.3-1.3 G. (5-20 grs.). Syrupus Acidi Citrici (U. S. P.) is ordinary syrup to which one per cent. ( citric acid and spirit of lernon have been added, and is used only as a flavoi Citric acid is used to form lemonades and effervescent draughts. Fc lemonade 2-4 parts of citric acid may be dissolved in 1,000 parts of watei some sugar and a few drops of volatile oil being added. For effervesce! solutions about 8 parts of the acid may be prescribed along with 7 parts < bicarbonate of soda, with directions to dissolve the two powders separately mix the solutions and drink while effervescing. In large quantities this mh tare acts as a saline cathartic ; in smaller quantities it may be used to ii crease the alkalinity of the blood, and to render the urine less acid. (Se pages 537 and 550.) Lime juice and lemon juice, which contain considerable amounts of fre citric acid, are generally preferred to the pure acid for lemonades to quenc the thirst. Lime juice has been found of great benefit as a prophylactic i the treatment of scurvy, but this is not due to the citric acid, but to som unknown property of the fruit juices. Citric acid has been used in rheumati affections, without any marked improvement being elicited, according to tt best observers. CALCIUM. 565 XIX. CALCIUM. The salts of lime are present in very large amount in the tissues of animals, and considerable interest attaches to their absorption, excretion and general action. They form the great mass of the inorganic con- stituents of the bones and teeth of the vertebrates and of the shells of the invertebrates. In addition it has been shown of recent years that they are present to a considerable amount in the soft tissues and are, in fact, essential to many forms of living matter, and to the activity of certain ferments. Calcium and the other alkaline earths differ from the alkalies in possessing comparatively few very soluble salts, and they seldom effect such changes in the physical properties of the fluids of the body as have been described under salt-action and chloride of sodium. Even the soluble salts penetrate with greater difficulty into the various tissues of the body, which seem to have much less affinity for them than for the salts of the alkalies. They precipitate colloids, such as the proteids, in much more dilute solutions than the alkalies, and the precipitate is not redissolved by dilution with water. Action. The soluble lime salts are Absorbed with great difficulty from the stomach and intestine, and retard considerably the absorption of fluid. They would presumably have a cathartic action were they not thrown out of solution very readily by the alkaline fluids. In addition calcium forms insoluble salts with all of the cathartic acid ions, so that no such double effect can be obtained as is seen from mag- nesium sulphate. (See Saline Cathartics, page 531.) The great pro- portion of the lime taken either in the food or as a remedy, unquestion- ably leaves the body in the stools entirely unabsorbed, while a small quantity of it is taken up from the alimentary canal whether the lime be administered in a soluble or in an insoluble form. This small quan- tity circulates in the blood, probably in combination with proteids, and is slowly excreted, unless there is a deficiency in the supply of lime, when it may be utilized by the tissues. When larger quantities are thrown into the blood by intravenous or hypodermic injection, the calcium of the blood remains abnormally high for some time, but all the calcium thus injected is not in the circulation throughout its stay in the body. Some of it is temporarily deposited in some unknown organ, and is gradually withdrawn and excreted after the first excess is eliminated. The lime is Excreted in part in the urine, but for the most part through the epithelium of the large intestine. Abel and Muirhead have shown that some of the calcium ingested in the form of the hy- drate is excreted in the urine as calcium carbamate (Ca(CO 2 NH 2 ) 2 ) and probably other salts may be eliminated in part at any rate in this form. The carbamate is a very unstable salt, and breaks up in the urine, freeing carbonic acid and ammonia, while the calcium forms the carbonate of lime ; the urine is often alkaline therefore, and smells strongly of ammonia. Calcium lessens the phosphates of the urine, 566 INORGANIC SALTS, ACIDS AND BASES. and therefore its acidity, by forming insoluble phosphates in the bowel, and thus preventing the absorption of the phosphates of the food. The small quantity of calcium absorbed from the alimentary canal has not been shown to have any action except in replacing the calcium compounds of the tissues. Except under special circum- stances, the calcium of the food is always sufficient to supply the needs of the organism, so that lime salts given as remedies have after absorp- tion no specific action due to the calcium, but owe their activity to the anion exclusively. Thus, calcium bromide may have some effect if absorbed, but this effect is due to the bromide ion, and would be the same if an equal proportion of sodium bromide were taken up by the blood. In the same way calcium hydrate when absorbed owes its ac- tivity to its alkalinity (hydroxyl ion) and not to the calcium, and apart from the method of its excretion, has the same effect in the tissues as an equivalent amount of sodium hydrate. Soluble calcium salts injected directly into the blood vessels seem to be poisonous, though further study of their action is required. They first accelerate and strengthen the heart, and in large quantities bring it to a stand- still, and also have a marked effect in contracting the vessels when perfused through them. They depress the central nervous system, causing narcosis and sleep, during which some authors state that the reflexes remain unaffected, while others found them much depressed. These effects are absent when the salts are taken up from the bowel, mainly no doubt owing to their slow absorption, partly perhaps to their forming albuminous compounds in their passage into the tissues. Lime Starvation. Excess of calcium in the organism is therefore little to be apprehended from the ordinary methods of administration, and lime salts are not used in therapeutics to induce changes in the organism through their presence in excess in the blood, like other remedies such as morphine or strychnine. Another question arises, however, namely whether the organism may not be rendered abnormal by a deficiency in the supply of lime, and whether this deficiency may be remedied by the administration of calcium salts. The effects of a deficiency of lime in the food have been the subject of several very careful investigations, and while the adult animal does not seem to suffer greatly from a very considerable reduction of the calcium of the food, young growing animals have at the hands of some investigators developed marked abnormalities, resembling closely those observed in rickets and osteomalacia in the human subject. In lime starvation, as in rickets, there is a lessened deposit of lime in the bones, which retain their cartilaginous consistency and show other deviations from the normal condition ; in rickets the bones alone are involved, while in animals deprived of calcium the soft tissues also show a lessened content of lime salts. Deficiency of the lime in the food naturally affects young animals more than adults, because the former require much more calcium to build up the growing skeleton. The effects of the withdrawal of lime have been studied in some Iso- lated Organs. Thus Ringer compared the behavior of the frog's heart when perfused with solutions of the salts of the alkalies with that of CALCIUM. 567 one perfused with the same solutions to which minute traces of lime were added, and found that the efficiency of the heart was much in- creased and that it survived very much longer under the latter condi- tions ; Locke has recently shown that a similar relation exists between the mammalian heart and the inorganic elements of serum. Lime salts exercise a similar effect in voluntary muscle, which survives much longer when perfused with salt solution containing calcium than when sodium chloride solutions alone are used. Both the heart and skeletal muscle eventually cease to contract on electrical stimulation when per- fused with physiological salt solution, but recover again when traces of lime salts are added to it. In the same way, the irritability of the frog's nerve persists much longer in salt solution containing a lime salt than in unmixed salt solution, and may be restored by the addition of lime, when it has disappeared after the prolonged action of the 0.6 per cent, chloride of sodium solution. Ciliated epithelium continues to wave rhythmically much longer in lime solution than in distilled water, in which it swells up and rapidly loses its activity. This prob- ably explains the observation that some fish die very soon in distilled water but survive in water in which traces of lime are present. Lime is also necessary for the development of various ova ; for instance, frog spawn kept in water devoid of lime salts fails to develop, or develops abnormally. Lime salts are also indispensable in some processes which are not dependent on the presence of living cells. Thus rennet does not coagu- late milk except when a lime salt is present, and the Coagulation of the Blood may be prevented by precipitating its calcium salts in the form of oxalates. Hammersten has recently shown that the lime salts are not necessary to the formation of fibrin, for this occurs in oxalate solutions if fibrin-ferment be added to fibrinogen. But the fibrin- ferment is not formed except in the presence of calcium salts, and when oxalates are added to the blood before this ferment is developed, they prevent its formation and hinder clotting. When lime salts are added, the ferment is liberated and coagulation occurs at once. In other words, lime is not necessary for the activity of the fibrin-ferment, but for its development from the prothrombin or zymogen, in which it ex- ists in the circulating blood. Other ferments act in the absence of available lime salts. Thus pepsin digests when instead of hydrochloric, oxalic acid is added to it, but it is unknown whether pepsin is formed from pepsinogen in the absence of lime. The higher organisms, both animals and plants, have thus been shown to require lime for some of their functions, and it is probably necessary for many others in which its importance has not yet been recognized. The lowest forms of life, however, including the bacteria and some of the moulds, seem to be able to live without it. In order to induce the effects of lime starvation, it is not always necessary to withdraw lime from the food, for they may be caused by the presence of any substance which prevents the dissociation of the calcium ion. 568 INORGANIC SALTS, ACIDS AND BASES. Thus, oxalate solutions added to the blood or milk, or to the nutrient fluid for perfusion of the heart, have the same effects as the withdrawal of lime. Food containing large quantities of oxalate salts has in some cases induced symptoms in animals resembling those of lime starvation, and it seems possible that some of the symptoms of fluoride action are also explicable from their precipitating the lime salts of the food and of the blood. In several instances a curious relationship has been shown to exist be- tween the calcium and potassium salts. Thus when a frog's heart is per- fused with sodium chloride solution containing a trace of calcium, the move- ments are not entirely normal, the contraction being somewhat prolonged and the relaxation much retarded. If a trace of potassium chloride is added, however, the contraction becomes normal in character. On the other hand the effect of potassium on the frog's heart is antagonized by the addition of lime. The same holds true for voluntary muscle, the salts of calcium tend- ing to neutralize the effects of potassium, and vice versa, and in several other relations an antagonism has been observed between these two metals. (See Ringer.) Another question that has excited much interest recently is the relation between sodium and calcium. It has already been noted that the frog's heart perfused with sodium chloride solution soon ceases to beat, but can be restored by the addition of calcium and potassium to the circulating medium. The ordinary explanation (Kinger, Howell) is that the calcium and potassium are necessary to the activity of the heart and that when pure salt solution is perfused, these elements diffuse into it and are lost from the heart muscle ; this diffusion is prevented if calcium and potassium be contained in the solution, and the heart, retaining the salts essential to its activity, continues to beat. Another explanation has been offered by Loeb, who supposes that the lime and potassium are not directly essential, but that they neutralize the poisonous effects of sodium. This poisonous action of sodium has not been generally recognized, but is well shown by the behavior of a small fish (fundulus) living in salt water, which can be transferred to distilled water without injury, thus showing that neither sodium nor calcium is necessary in its environment. But if it be put in sodium chloride solution of the same strength as sea water it dies, so that sodium is poisonous to it unless when antagonized by the other constituents of sea water ; the essential elements are calcium and potassium, for when these are added to the injurious sodium solution, the fish lives as well as in sea water. This series of experi- ments certainly forms a strong support for Loeb's theory that calcium is not directly essential to rhythmic movement, but only neutralizes the effects of sodium. On the other hand, the calcium salts themselves are poisonous when they are not counterbalanced by sodium and potassium ; in this, as in many other instances, there must be maintained between the inorganic constituents of the surrounding fluid an equilibrium, such as exists in sea water, in the case of the fundulus and in the blood plasma in the case of the heart and other organs. The salts of the alkaline earths are said to inhibit the hsemolytic action of cer- tain serums, while those of the alkalies have not this effect when applied in the same concentration ; this may perhaps be connected with the tendency the former have to coagulate proteids. The formation of proteid combinations is apparently the explanation of the disappearance of lime salts when they are perfused through organs or when pieces of tissue are soaked in them. Therapeutic Uses. Calcium salts are used in medicine for a number of different purposes ; thus the alkaline preparations may be prescribed to lessen the acidity of the stomach, and the oxide may be employed as a caustic. But these owe their use, not to the calcium ion, but to the CALCIUM. 569 other part of the molecule the anion. As a matter of fact, calcium has no important effects of its own and is not prescribed for any action which it might have on the living tissues. The question has been raised, how- ever, whether calcium may not be given therapeutically to supply a deficiency of lime in the body. The particular conditions which have been treated on this theory are rickets and osteomalacia, in both of which there is unquestionably too little lime in the bones, and the treat- ment has been thought to be rational, because symptoms similar to those of rickets have been induced in young animals whose food con- tained too small a proportion of lime. In the case of rickets and os- teomalacia, however, there is no reason to suppose that the food is deficient in calcium; in fact, children are said to be more liable to rickets when fed on cows 7 milk than when nursed by the mother, al- though the milk of the cow contains more lime. On the other hand, patients suffering from rickets absorb lime and excrete it again in ex- actly the same way as normal persons, and although their bones con- tain unusually small amounts of lime, the other tissues contain rather more, or, at any rate, not less than normal. Rickets is not due to a lack of lime in the food, therefore, nor in fact in the tissues generally, but to some abnormal condition which prevents the lime salts from being deposited in the bones, although they are present in abundance in the blood. In cases of lime starvation similar symptoms may ap- pear, but here the cause is the want of lime, which is not presented in sufficient quantities, although the bone-forming cells are ready to de- posit it. In this case the other tissues are also deficient in calcium as well as the bones. From these considerations it follows that lime salts are not likely to be of benefit in rickets (nd the same holds true for osteomalacia), unless when it is due to lime starvation, a condition which is unlikely to arise in the human subject. Experience has demonstrated also that the lime salts are quite incapable of improving either osteomalacia or rickets. It has also been proposed to treat with lime cases in which the blood seemed less capable of clotting than normally particularly haemophilia and aneurism, and some improvement is said to have occurred in a few instances. Here again, however, it would seem to be very improbable that the absence of coagulation is due to deficiency in the lime salts, for much more is taken in the food than is sufficient for the organism, and the pharmacopoeial salts are not more easily absorbed than the combinations present in food. More recently the treatment has been extended to forms of haemorrhage in which there is no reason to sup- pose that the coagulability of the blood is reduced haemoptysis, gas- tric and intestinal haemorrhage. The value of the treatment cannot be estimated accurately, owing to the tendency to spontaneous arrest always present in these hemorrhages ; but the results, while not decisive, do not appear very encouraging. Another treatment of aneurism and haemorrhage of recent introduc- tion is GELATINE administered by the mouth or hypodermically (100 c.c. of a 15 per cent, solution). This is based on a series of experiments 570 INORGANIC SALTS, ACIDS AND BASES. which seemed to indicate that the coagulation of the blood is hastened by gelatine, but which have not been confirmed by later investigators^ who have found, that while the blood sometimes clots more rapidly than usual in the presence of gelatine, as a general rule the process is nol changed in rate. Gelatine has been used very extensively in the lasi few years, and some clinicians report favorable results, but in the hands of others it has failed to influence the course of the disease. Aneurism of the aorta, haemoptysis, gastric, intestinal, renal, and uter- ine bleeding have all been treated with gelatine with very doubtful benefit. In some cases gelatine has proved the channel of infection by tetanus. It has been applied to still local haemorrhage from the mouth and nose, but has been supplanted here by adrenaline. Gelatinum (U. S. P.), purified gelatine. Gelatinum Glycerinatum (U. S. P.), gelatine impregnated with an equal weight of glycerin. PREPARATIONS. Calcii Chloridum (U. S. P., B. P.) (CaCl 2 ), a white salt with a sharp, saline taste, very deliquescent and soluble in water. 0.3-1 G. (5-15 grs ). Calcium chloride is the salt which gives the least complicated calcium ac- tion, and is consequently seldom used, because, as has been explained, the calcium ion is of comparatively little service in therapeutics. It has a strong attraction for water and is therefore more irritant than the other chlorides of the alkalies and alkaline earths, and ought to be prescribed only in dilute solution. It is absorbed with great difficulty, and has been suggested in the treatment of some forms of dyspepsia and in haemorrhage. Calx (U. S. P., B. P.) (CaO), unslaked lime, is a corrosive and disinfectant, and is changed at once to the hydrate in the presence of water. It differs from the caustic alkalies in the insolubility of its hydrate, which therefore fails to penetrate deeply and does not spread so widely as potassium and sodium hydrates. It is seldom employed alone as a corrosive, but mixed with potassium hydrate as Vienna paste (Potassa cum Calce, U. S. P.) has had some popularity. It is used as a disinfectant where large quantities of organic matter have to be rendered harmless, as in epidemics, on battle fields and in the dejec- tions of large hospitals. It ought to be mixed with the matter to be disin- fected, as thoroughly as possible. Lime possesses the advantage over other disinfectants of being cheap and easily procurable in large quantities. Calcii Hydras (B. P.), slaked lime (Ca(HO) 2 ), may also be used as a disin- fectant. LIQUOR C ALOIS (U. S. P., B. P.), lime water, is a saturated solution of calcium hydrate or slaked lime and contains about 0.17 G. in 100 c.c. ( gr. in 1 oz. B. P.). It is a clear fluid with a saline and feebly caustic taste. 30-100 c.c. (1-4 fl. oz.). SYRUPUS CALCIS (U. S. P.), LIQUOR CALCIS SACCHARATUS (B. P.), syrup of lime, contains calcium hydrate kept in solution in water by sugar, with which it is probably combined chemically. The amount of lime contained varies greatly, but is much larger than in lime water. The B. P. prepara- tion is said to contain nearly 2 per cent, by weight, or 8 grs. to the oz. 1-4 c.c. (15-60 mins.). LINIMENTUM CALCIS (U. S. P., B. P.), lime liniment, or Carron oil, con- tains equal parts of lime water and olive or linseed oil. These preparations owe their activity chiefly to their alkalinity and not to the calcium, but differ from the hydrates of the alkalies in their insolubility and in their slow absorption. Lime water and the syrup CALCIUM. 571 are slightly caustic, more especially the latter, and tend to neutralize the gastric juice. They have an astringent effect in the intestine which has not yet been explained, but is probably due to their forming an insoluble compound with the surface proteids, in the same way as tannic acid, or to their being deposited as the carbonate or phosphate and thus protecting the epithelium from irritation. Lime water is used in some dyspeptic conditions, especially in vomiting. It is often added to milk in intestinal irritation in children and in typhoid fever, as it is found that milk thus treated coagulates in finer particles than when given alone, and is better digested and less liable to disturb the intestine. Lime water or syrup of lime is also used as an intestinal astringent in diarrhoea, especially in children. As an antacid in the stomach, lime is .inferior to magnesia and other alkalies, because it tends to delay the evacuation of the contents. Lime water has been used in rickets, which seems singularly irrational, for cows' milk con- tains a somewhat higher percentage of lime. It has also been sprayed against the false membrane of diphtheria, which it is said to dissolve. Lime water is not applicable in cases of acid poisoning, as it contains much too little of the base to be serviceable, but the syrup may be used, or lime shaken up with water (milk of lime). The treatment with lime is specially indicated in cases of oxalate poisoning. Lime water has been used externally as a protective, mildly astrin- gent application to ulcers, and the lime liniment has been largely used in the treatment of burns. It derives its name of Carron oil from having been used for this purpose in the iron works at Carron. Calcii Carbonas Pr&cipitatus (U. S. P., B. P.), precipitated chalk (CaCO 3 ). 1-4 G. (15-60 grs.). Greta Prssparata (U. S. P., B. P.), prepared chalk, chalk purified by washing and suspension in water (CaCO 3 ). 1-4 G. (15-60 grs.). PULVIS CRET.E COMPOSITUS (U. S. P.), a mixture of prepared chalk, sugar and acacia. 5-10 G. (1-2 drs.). PULVIS CRET.E AROMATICUS (B. P.), aromatic chalk powder, contains chalk along with sugar and a number of carminatives belonging to the group of volatile oils. 10-60 grs. PULVIS CRET^; AROMATICUS CUM OPIO (B. P.) is a mixture of 39 parts of the aromatic powder with one of opium, and therefore contains 2J per cent, of opium. 10-40 grs. MISTURA CRET^: (U. S. P.), chalk mixture, is chalk suspended in water by means of gums. 15-30 c.c. (J-l fl. oz.). The preparations of the carbonate of lime are used as antacids in hyperacidity of the stomach, especially when this is combined with a tendency to diarrhoea. The mixture or the aromatic powder B. P., is the form generally used, and may be prescribed with opium or with other astringents. Chalk has also been used in rickets. Externally, prepared chalk is used as a powder to protect irritated parts of the skin and occasionally in ulceration ; it is the chief in- gredient in most tooth powders. In older treatises on therapeutics, great virtues are ascribed to various natural objects which are com- posed for the main part of chalk or other salts of lime, and among 572 INORGANIC SALTS, ACIDS AND BASES. which burned bones, coral, coralline, and cuttlefish bone may be men- tioned. Calcii Phosphas Prsecipitatus (U. S. P.), Calcii Phosphas (B. P.) (Ca 3 (PO 4 ) 2 ), a white insoluble powder. 0.3-1 G. (5-15 grs.). Syrupus Calcii Lactophosphatis (U. S. P., B. P.), a preparation in which a soluble double salt of lime is contained in solution. 2-4 c.c. (J-l fl. dr.). A glycerophosphate of calcium has also been advised recently. These phosphate preparations have been used in rickets and osteomalacia, and in phthisis and other tubercular diseases, but the best authorities are agreed that lime salts are of no value in rickets and osteomalacia (see page 573), and experience with them in tubercular conditions is not more encouraging. Calcii Bromidum (U. S. P.) (CaBr 2 ) has been used as a substitute for the more commonly used bromide of potassium, and is administered in the same dose. It is more slowly absorbed and therefore inferior to the alkaline bro- mides, and is entirely superfluous. Calcii Sulphas Exsiccatus (U. S. P.). Dried calcium sulphate or dried gyp- sum contains 95 per cent, of sulphate of calcium (CaSO 4 ) and 5 per cent, of water. It is used exclusively to form immovable bandages in surgery (plas- ter of Paris bandages). BIBLIOGRAPHY. See Oxalates and Sodium Chloride. Jankau. Arch. f. exp. Path. u. Pharm., xxix., p. 237. Raudnitz. Ibid., xxxi., p. 343. Abel u. Muirhead. Ibid., xxxi., p. 15. Radel Ibid., xxxiii., pp. 79, 90. Rey. Ibid., xxxv., p. 295. Deutsch. med. Woch., 1895, p. 569. Brubacher. Zts. f. BioL, N. F., ix., p. 516. F. Voit. Ibid., xi., p. 325. Weiske. Ibid., xiii., p. 421. Ringer. Journ. of Physiol., iii.-xvi. Howell (and pupils). Ibid., xiv., p. 198 ; xvi., p. 476. Amer. Journ. of Phys., v., p. 338 ; vi., p. 181. Loeb, Lingle, Lillie, Moore. Amer. Journ. of Phys., iv., p. 265 ; v., pp. 56, 87, 362 ; vi., p. 411. Loew. Ein natiirliches System der Giftwirkungen, 1893, p. 33. Kitasato. Zts. f. Hygiene, iii., p. 404. Pfuhl. Ibid., vi., p. 97. BineL Comptes rendus d. 1'Acad. de Science, cxv., p. 251. Bayer. Med. News, 1886, ii., p. 253. Vierordt. Nothnagel's Specielle Pathologic und Therapie, vii. Hammarsten. Ztschr. f. phys. Chem., xxii., p. 333. Strauss. Ztschr. f. klin. Med., xxxi., p. 493. Miwa u. Stoeltzner. Ziegler's Beitriige zu Path., xxiv., p. 578. XX. BARIUM AND STRONTIUM. Barium is the most poisonous of the three common alkaline earths, but resembles the others in penetrating with difficulty into the epithelium of the alimentary canal, and is therefore absorbed very slowly. It has a charac- teristic action on many forms of muscular tissue, resembling closely that of veratrine, and the contraction of the frog's muscle under barium is thus stronger than normally, and is very greatly prolonged. The frog's heart beats more strongly, but more slowly from a similar action on the muscle fibres, and the walls of the stomach and intestine are thrown into violent contraction from the action of the metal on the unstriated muscle fibre. There is some question as to whether the central nervous system is acted on in the frog, but in the mammal barium salts injected intravenously cause violent tonic and clonic spasms, from their stimulating the spinal cord and medulla oblongata. The action on the alimentary canal induces vomiting and purging with very active peristalsis. The heart is accelerated, and the SULPHIDES AND SULPHUR. 573 blood-pressure is enormously increased at first, and then undergoes slow undulations for gome time. The increased tension may be due to the cardiac action in part, but is chiefly to be ascribed to a very marked contraction of the muscular walls of the vessels. The frog's heart eventually assumes an irregular peristaltic form of contraction and ceases in systole, as in digitalis poisoning, and the changes in the mammalian heart also resemble those caused by this series. Barium in sufficient quantities finally paralyzes the central nervous system. In fatal poisoning in animals, haemorrhages have been found in the stomach, intestine, kidney and other organs. Barium is quite incapable of replacing calcium in its relations to living matter, and accordingly chloride of sodium solutions to which barium chlo- ride has been added do not tend to keep the frog's heart active as do those containing lime. Some authors hold that barium can replace calcium to an imperfect degree in the coagulation of the blood, but this is denied by others. Potassium salts tend to neutralize the effect of barium on the heart and mus- cles, the relation resembling that which they bear to lime. Barium is absorbed slowly from the intestine, and is found to be stored in the bones to some extent, and to be excreted in the urine and probably in the bowel. It has been suggested as a treatment for different forms of tremor, but has seldom been used in practical therapeutics. BIBLIOGRAPHY. Boehm, Arch. f. exp. Path. u. Pharm., iii. , p. 216. Neumann. Pfliiger's Arch., xxxvi., p. 576. Bruntonand Cash. Phil. Trans, of Roy. Soc., 1884, i., p. 223. Binet. Comptes rend. d. PAcad., cxv., . 251. See also Bibliography of Calcium, Potassium, Rubidium and Caesium. Strontium is a comparatively inert substance even when injected directly into the blood, resembling calcium in its action in the body as far as is known, but being even less poisonous. It contracts the muscles somewhat, tends to lessen the dilation of the heart, and prolongs the contraction of muscle, though only to a slight extent. It is absorbed very slowly from the intestine like the other alkaline earths, find is deposited in small quantities in the bones of growing animals, especially when there is a deficiency of lime in the food. It is excreted in small quantities by the urine, but mainly by the bowel. Strontium salts have been used to a limited extent in thera- peutics, not for the effect of the strontium ion, but for the bromide, iodide or salicylate effects of its salts. In view of the fact that the strontium salts are more slowly absorbed than the corresponding ones of sodium and potas- sium, there would seem to be good grounds for abandoning their use. PREPARATIONS. U. S. P. Sirontii Bromidum (SrBr 2 + 6H 2 O), 1-4 G. (30-60 grs.). Strontii lodidum (SrI 2 + 6H 2 O), 0.3-1 G. (5-15 grs.). Strontii Lactas (Sr(C 3 H.O 3 ) 2 -f 3H 2 O), 1-2 G. (15-30 grs.). BIBLIOGRAPHY. See Calcium, Barium. Wood. Amer. Journ. of Physiol., i., p. 83. Mendel and Thacher. Ibid., xi., p. 5. XXI. SULPHIDES AND SULPHUR. The ordinary sulphides of the alkalies are of little importance in* themselves, as they are seldom used in therapeutics. The eifect of hydrosulphuric acid, however, apart from its local irritant action, is due 574 INORGANIC SALTS, ACIDS AND JBASES. to the sulphide which it forms in the blood, and the study of this powerful poison therefore involves a preliminary examination of the effects of the sulphides. Again, sulphur is in itself inert, but is changed to sulphides and hydrosulphuric acid in the alimentary canal, and the effects induced by its administration are due to these bodies, and not to the original element. Action. The sulphides are very weak salts, for even carbonic acid is capable of liberating hydrosulphuric acid, and wherever they come in con- tact with it in quantity, there is a tendency to form free acid, which acts as a powerful local irritant ; it is not impossible that the sulphides have an irritant effect of themselves in addition to that of the hydrosulphuric acid. The sulphides accordingly act as irritants in the stomach and bowel, and in the latter induce increased peristalsis and purgation. When injected sub- cutaneously in the frog, sodium sulphide causes a narcotic condition from depression of the central nervous system, and in sufficient quantities weakens the skeletal muscle and the heart, which continues to beat after complete paralysis has been obtained, but eventually ceases in diastole. Harnack has recently shown that after the narcosis has lasted for some time, a new con- dition follows, if only small quantities have been given, and especially if the frog is healthy and is kept cool. This consists in an enormous increase in the reflex irritability, which induces convulsions resembling those of strych- nine poisoning in their general character, but differing from them in lasting continuously for weeks or even months at a time. The animal lies in an ex- tended and tense condition throughout, and passes into complete opisthotonos on being touched. Sulphides injected intravenously in mammals induce violent convulsions, which seem to be of cerebral origin, for they do not occur in the hind limbs when the spinal cord is cut. The respiration is at first accelerated and latei dyspnceic and finally ceases, this along with the paralysis of the vaso-motoi centre being the cause of death. The heart does not seem to be seriously affected except indirectly through the failure of the respiration and the fall of the blood-pressure. Sulphide solutions added to drawn blood reduce the oxyhsemoglobin at once, and give the blood a dark venous color. At the same time a compound of sulphide and haemoglobin is formed, the chemistry of which is still very obscure, but which would seem to be more nearly related to methsemoglobin than to haemoglobin. It is known as sulpho-hsemoglobin or as sulpho-met- hsemoglobin, and gives the blood a greenish color when a thin layer is ex- amined, while a thicker layer is dark red-brown. This sulpho-hsemoglobin possesses a characteristic spectrum, marked by a dark line in the red to the left of the D line. Larger quantities give an olive-green color to the blood, and the spectrum of sulpho-hsemoglobin disappears. When sulphides are injected into frogs, and more especially when sulphuretted hydrogen is in- haled, the blood gives the characteristic spectrum during life, but this does not seem to be the case in mammals, although sulpho-hsemoglobin is formed soon after death. The blood changes are not the cause of death in poison- ing, as was formerly supposed, but the direct action of the sulphides on the central nervous system. Sulphides absorbed into the blood are rapidly oxidized, and are excreted in the urine in the form of sulphates and of organic sulphur compounds of un- known constitution. Small quantities escape by the lungs, and give the breath the disagreeable odor of sulphuretted hydrogen, and according to some authorities, some is excreted in this form in the perspiration. The sulphides dissolve the horny epidermis and hair very readily when they are applied to the skin. If the application is continued, some irritation and redness is produced. SULPHIDES AND SULPHUR. 575 Hydrosulphuric Acid (sulphuretted hydrogen, hydrogen sulphide (H ? S)) differs from the sulphides in being a gas, and in its strong irritant properties, which it shares with other acids (see page 555). It has not infrequently given rise to poisoning, as it is formed in large quantities in the course of the putrefaction of sulphur compounds, such as proteids. Sewer gas often con- tains it in quantity, and workmen employed in cleansing sewers or cesspools have often suffered from its effects. When inhaled in concentrated form it is almost immediately fatal, the patient losing consciousness at once, and the respiration ceasing after a few seconds. In smaller quantities it causes im- mediate unconsciousness, lasting for several hours and then passing into fatal coma, which is often interrupted by violent convulsions. In both of these forms the symptoms are due to the direct action of the sulphides on the brain and medulla oblongata. Persons exposed to a very dilute vapor of sulphur- etted hydrogen suffer from local irritation of the eyes, nose and throat, indi- cated by pain and congestion of the conjunctiva, sneezing, dryness and sore- ness of the mouth and throat, and a reflex increase in the secretion of tears, saliva and mucus. Headache, dulness, giddiness and loss of energy are com- plained of; the symptoms frequently appear only some time after the ex- posure to the poison. According to Lehmann, death in animals exposed to these dilute fumes is due in part to oedema of the lungs caused by the local irritant action. He fouad that one part of hydrosulphuric acid in 5,000 of air was sufficient to induce symptoms in man, and that an atmosphere con- taining one part in 2,000 could be respired for only a short time, and gave rise to alarming symptoms ; he supposes that about one part of hydrosul- phuric acid in 1,000 parts of air is sufficient to poison man fatally in a very short time. The poisonous effect of sulphuretted hydrogen is due in part to its local irritant action, in part to its directly affecting the central nervous system. The changes in the blood occur during life only after very concentrated gas is inhaled, although they may indicate the poison after death from more dilute vapor, for the tissues in general tend to assume a green color sooner after hydrosulphuric acid poisoning than in the course of ordinary putrefaction. Hydrogen sulphide is destructive to most forms of life, even when present in comparatively small amount. Even the microbes of putrefaction, which produce it themselves, are eventually killed by this gas, unless it escapes freely. PREPARATIONS. Potassa Sulphurata (B. P. ), liver of sulphur (Hepar Sulphuris), is a mixture of polysulphides and thiosulphates, often containing sulphate of potassium. The greater part is formed of potassium trisulphide (K 2 S 3 ) and of potassium thio- sulphate (K 2 S 2 O 3 ). It is soluble in water and possesses an unpleasant saline taste, and an odor of hydrogen sulphide, which is formed by its decomposition in water. Calx Sulphurata (U. S. P., B. P.), sulphurated lime, is another impure preparation containing at least 60 per cent, of calcium monosulphide (CaS) (50 per cent. B. P.), with some calcium sulphate and charcoal. It forms a grayish powder, insoluble in water, and gives off hydrogen sulphide. 0.015 -0.06 G. (J-l gr.). These preparations are seldom used internally, and, in fact, the sulphur- ated potassium has been found to be a dangerous poison, from the hydrogen sulphide given off .by it in the bowel acting both locally and after absorption. Sulphurated potassium is used to a very limited extent as an external appli- cation in certain skin diseases, particularly in acne, and to destroy skin parasites, such as that of scabies. It is used as an ointment (1 part to 10 parts), and is somewhat irritant. Sulphurated lime is used occasionally to remove hair and horny excres- cences, both of which it renders soft and gelatinous, but its frequent use is liable to cause irritation. 576 INORGANIC SALTS, ACIDS AND BASES. Hydrogen sulphide has been used in the treatment of pulmonary phthisis, the gas being applied by the rectum, but the treatment was followed in sev- eral cases by serious symptoms of poisoning, and has not been shown to be beneficial. Very small quantities only escape by the lungs. Many mineral springs contain hydrogen sulphide in small amount, and these have obtained wide celebrity in the treatment of various chronic res- piratory and skin diseases and in syphilis, gout, rheumatism and chronic metallic poisoning (lead, mercury). Most of these springs are hot, and it is open to question whether the small amount of the gas contained in the water is of any efficacy, and whether the heat of the water and the hygienic conditions are not the true cause of the improvement observed in these cases, Sulphur baths are also formed artificially by the addition of sulphuratec potassium (2-8 oz.) to an ordinary hot bath ; a small quantity of acid is some- times added, in order to free the hydrogen sulphide more rapidly. Sulphur is in itself an inert body, but while much the greater portior escapes in the stools unchanged when it is swallowed, some of it forms sulphides in the mucous membrane of the intestine, and these cause irritation, increased peristalsis, and mild purgation ; in large quantities it has caused, in some instances, more severe symptoms with bloody evac- uations. The sulphides form some hydrogen sulphide, which gives rise to eructation. Some 10-20 per cent, of the sulphur taken by the mouth is absorbed as sulphide, which is excreted to a small extent by the lungs, giving the characteristic disagreeable odor to the breath, and tc a mnch larger extent by the urine as sulphates and in organic combi- nation. In one experiment, Presch found the urea of the urine con- siderably increased (10 per cent.) under sulphur, and Umbach found it increased by pure calcium sulphide ; whether, as this would suggest, the sulphides augment the nitrogenous waste as a general rule, can only be determined by further experiment. Applied to the skin in ointment, sulphur appears to be formed in part to sulphide, particularly if some alkali be added. PREPARATIONS. Sulphur Sublimatum (U. S. P., B. P.), Flowers of Sulphur, sublimed sul- phur. Sulphur Lotum (U. S. P.), washed Flowers of Sulphur, is prepared bj washing the sublimed sulphur with water and ammonia. These prepara tions form fine yellow powders insoluble in water and very slightly soluble in alcohol. 1-4 G. (15-60 grs.) in powder or sometimes in tablets. Sulphur Prsecipitatum (U. S. P., B. P.), Milk of Sulphur, is prepared fron sulphide of calcium by precipitation and forms a fine, almost white powdei without odor or taste, insoluble in water, and only very slightly soluble ir alcohol. 1-4 G. (15-60 grs.). Unguentum Sulphuris (U. S. P., B. P.), formed from sublimed sulphur, which is also contained in the Compound Liquorice Powder. Trochiscus Sulphuris (B. P.) contains 5 grs. of sulphur. Confectio Sulphuris (B. P.), 60-120 grs. Thilanin (non-official) is a mixture of lanolin and sulphur containing aboui 3 per cent, of the latter, and has been proposed as a substitute for the oint ment. Crude sublimed sulphur often contains arsenic and other impurities, anc ought not to be used in therapeutics. The milk of sulphur is in a finei state of division than the flowers, and is said to be a somewhat more active aperient. SULPHIDES AND SULPHUR. 577 SulphuT is used as an aperient powder, and may be added to rhu- barb or magnesia for this purpose ; it causes a soft, formed stool, and seldom induces more than one evacuation. It is prescribed for chil- dren, and in cases of haemorrhoids, in which it is often very beneficial, not owing to any specific effect on the haemorrhoids, but because it renders the stool softer and less liable to cause irritation mechanically. Sulphur has been advised in a variety of constitutional diseases and in chlorosis, skin and joint affections, but it is impossible to state at present whether it has any effect in these apart from its improving the condition of the intestine. Sulphur ointment has been used in some skin diseases, particularly xn scabies, but has been supplanted to a large extent by the balsam of Peru. It has been applied in powder to diphtheritic membranes. BIBLIOGRAPHY of Sulphides and Sulphur. Kaufmann u. Rosenthal Arch, f . Anat. u. Phys. , 1865, p. 659. Lewin. Virchow's Arch., Ixxiv., p. 220. Lehmann. Arch. f. Hygiene, xiv., p. 135. Pohl. Arch. f. exp. Path. u. Pharm., xxii., p. 1. Harnack. Ibid., xxxiv., p. 156. Ztschr. f. phys. Chem., xxvi., p. 558. Regensburger. Ztschr. f. Biol., xii., p. 479. Presch. Virchow's Arch., cxix., p. 148. Uschinsky. Zts. f. phys. Chem., xvii., p. 220. Binet. Trav. des Lab. de Ther. exp. de Geneve, ii., p. 242. Umbach. Arch. f. exp. Path. u. Pharm., xxi., p. 166. Meyer. Ibid., xli., p. 325. Heffter. Beitr. z. chem. Phys. u. Path., v., p. 213. Arch. f. exp. Path. u. Pharm., li., p. 175. Thiosinamine. Thiosinamine (CS-NH 2 -NHC 3 H 5 ) has recently been intro- duced into therapeutics in the treatment of scar tissue of many different forms. It is a comparatively inactive body in normal tissues, but large doses in animals induce tremor, vomiting, weakness, and deep sleep with slow, deep respiration. The central nervous system is first stimulated and then depressed. Fatal doses in animals induce oedema of the lungs and hydrothorax, and in frogs anasarca is generally present. Thiosinamine forms colorless, bitter, odorless crystals which are readily soluble in alcohol, less so in water. It is used to induce softening and absorption of cicatricial tissue in the skin and internal organs, and may be applied locally as a 10 per cent, plaster or ointment to the skin, but is much more frequently injected hypodermically in 15 percent, solution in alcohol, about 1 c.c. (15 mins.) being injected each day. It has also been given internally in capsules. Almost every form of cicatrix, whether following acute or chronic inflammation or surgical operation, has been treated with thiosinamine, and many very favorable results have been reported. In most of these cases there was no possibility of verifying the results by direct observation, but more satis- factory evidence has recently been adduced in cicatricial conditions in the eye, in which relief was obtained. No explanation of the action has as yet been suggested. BIBLIOGRAPHY. Dollken. Arch. f. exp. Path. u. Pharm., xlvii., p. 321. Lewandowski. Therap. d. Gegenwart, 1903, p. 441. Suker. Journ. Amer. Med. Ass., Aug. 9, 1902. . 37 578 INORGANIC SALTS, ACIDS AND BASES. XXII. CHARCOAL. Charcoal, like spongy platinum and other porous bodies, possesses the property of accumulating gases in its interstices and thus ordinarily contains considerable quantities of oxygen. When brought into contact with decom- posing matter, the oxygen is released and hastens the oxidation of the putre- fying mass, while the gases arising from the bacterial action are absorbed by the charcoal which thus acts as a deodorant. It has no direct action on the microbes of putrefaction, but may by introducing oxygen favor the develop- ment of the aerobic organisms at the expense of the anaerobic. Besides gases, charcoal also absorbs many colloid bodies, such as the coloring matter of plants and proteids. Animal charcoal appears to possess no advantages over wood charcoal, and they both act when moist almost as efficiently as in the dry state. Charcoal has no appreciable effect on the economy, apart from its lessen- ing the eructation of gas and the flatulence in some cases. It passes through the stomach and intestine unabsorbed, and may in rare cases cause some mechanical irritation and increased movement. Charcoal given in a state of suspension to animals is said to have been found in the epithelial cells of the intestine and even in the blood vessels, but does not have any effect attribut- able to its absorption in man. (Wild. Med. Chronicle, 1896.) PREPARATIONS. Carbo Animalis (U. S. P.), animal charcoal, bone-black, prepared from bone. Carbo Animalis Purificatus (U. S. P.) is prepared by boiling bone-black with hydrochloric acid in order to remove the lime and other impurities. Carbo Ligni (U. S. P., B. P.) Charcoal prepared from soft wood and finely powdered. Charcoal is used internally to remove the gases in flatulence and dyspep- sia, and is prescribed in powder or in the form of charcoal lozenges. It may be given in any quantity, but is most commonly prescribed in 4-8 G. (60- 120 grs.) doses. It is employed externally as a deodorant in cases of foul ulcers, cancerous sores, or malodorous secretions from any source ; for this purpose it is added to poultices or used dry in bags of fine cloth. XXIII. BORACIC ACID AND BORAX. Boracic or boric acid (B(OH) 3 ) is a very weak acid, and it is doubt- ful whether the hydrogen ions or acidity play any part in its action, or whether the whole is not to be referred to the rest of the molecule. The ordinary sodium compound, borax, Na 9 B 4 O 7 , is stated by some authors to be equally active, but is alkaline in reaction, so that the exact relative importance of the two ions of boric acid cannot be de- termined. Action. Boracic acid and borax are only feebly toxic, but large quantities taken by the mouth cause gastric and intestinal irritation, as is evidenced by vomiting and purging, and even smaller amounts are said to act as mild aperients in some cases. In animals muscular weak- ness and collapse, and, it is said, nephritis and albuminuria have been elicited by the injection of poisonous doses. Moderate doses are with- out effect on the metabolism/ but larger quantities (5-10 G. per day in dogs) increase the nitrogen excretion in the urine. In ordinary amounts borax does not affect the digestion and assimilation of food, but larger doses increase the bulk of the fa3ces by retarding the absorption of the BORACIC ACID AND BORAX. 579 proteids and fats. 1 Both borax and boracic acid are rapidly absorbed by the bowel, and do not affect the intestinal putrefaction. Boracic acid has been widely used as an antiseptic dressing, and a number of cases of serious poisoning have been recorded from its ab- sorption. The symptoms arose in part from the alimentary canal, uneasiness in the abdomen, vomiting, diarrhoea, dry ness of the throat and difficulty in swallowing ; sleeplessness, great muscular weakness and depression, dimness of sight, and headache were also complained of, and in severe cases collapse and death followed. The prolonged use of boracic acid, internally or externally, has repeatedly led to scaly skin diseases, eczema, psoriasis and alopecia. Papular eruptions and local cedemas and swelling of the skin appear, and a dark line on the gums, similar to that seen in lead poisoning, is stated to occur along with irritation of the mouth. These skin affections appear also when borax is used in large quantities as an antiseptic dressing. Boracic acid and borax are excreted in the urine, in which they appear within a few minutes after ingestion ; over half the quantity taken is excreted within 12 hours, but afterward the elimination proceeds more slowly, so that traces may be found in the urine for 5 days or more. It is sometimes stated that the urine is increased by borax, but this is not borne out by experiment, and Chittenden and Gies found it actually diminished in amount; the reaction becomes alkaline after sufficient amounts of borax, as after any other alkaline preparation. Boracic acid and borax have some antiseptic power, for in 2J per cent, solution almost all forms of bacilli stop growing; but they are not destroyed, even the delicate anthrax bacilli being found capable of further growth after exposure to a 4 per cent, solution for 24 hours. Boracic acid is therefore valueless as a disinfectant, but has been used as an antiseptic dressing ; it has the advantage over many other anti- septics of inducing very little irritation and of being only slightly poisonous, but experience has shown that it cannot be used with im- punity in very large quantities. PREPARATIONS. Acidum Boricum (U. S. P., B. P.), Boric or Boracic Acid (H 3 BO 3 ), color- less crystals, with a faintly bitter taste, soluble to about four per cent, in water, more so in alcohol and glycerin. 0.3-1 G. (5-15 grs.). Glyceritum Boroglycerini (U. S. P.), Glycerinum Acidi Borici (B. P.). Boro- glycerin is a compound formed by heating boric acid in glycerin, and the official glyceritum or glycerinum contains this dissolved in glycerin, about 31 parts of boric acid being used to form 100 parts. Liquor Antisepticus (U. S. P. ), containing 2 per cent, of boric acid, along with benzoic acid, thymol, eucalyptol, and oils of peppermint, wintergreen and thyme. Unguentum Acidi Sorici (B. P., U. S. P.), 10 per cent. Sodii Boras (U. S. P.), Borax (B. P.), Borax (Xa 2 B 4 O 7 + 10H 2 O) forms colorless crystals with a sweetish alkaline taste. It is soluble in water (16 parts) to which it gives an alkaline reaction. 0.3-1.3 G. (5-20 grs.). Glycerinum Boracis (B. P.) (1 in 6). Mel Boracis (B. P.). 1 The body weight often falls under borax treatment, and this has been attributed to augmented fat destruction by Eost and Rubner, who state that a corresponding increase in the carbonic acid elimination accompanies it. 580 INORGANIC SALTS, ACIDS AND BASES. Boracic acid has been used as a surgical antiseptic in solution (four per cent.), ointment, or lint, and the solution of the acid or of borax is also used as a wash in aphthe and other forms of irritation of the mouth. Boracic acid solution has been given internally in dilute watery solution as a genito-urinary disinfectant, has also been injected into the bladder, and is frequently used in ophthalmic surgery, as be- ing less irritant to the eye than the more powerful antiseptics. In internal medicine the acid and the salt have been used in epilepsy, and also in the hope of dissolving uric acid calculi, but have not been shown to be efficient for either purpose. Boracic acid and borax are sometimes added to milk or other food as preservatives, and it has been much discussed whether the habitual use of such preserved foods is likely to prove deleterious to the health. The general result of the investigations is that while no preservative should be added to food unless it is absolutely unavoidable, boric acid is less liable to derange the health than most other preservatives. Foods preserved with boracic acid should not be used by delicate individuals or by children, however, and the quantity of the acid used must be strictly limited. BIBLIOGRAPHY. Neumann, Arch, f. exp. Path. u. Pharm., xiv., p. 149. Forster. Arch. f. Hygiene, ii., p. 75. Rost u. Sonntag. Arb. a. d. Kais. Gesundheitsamte, xix., p. 110. He/ter. Ibid.j xix., p. 97. Fere, Semaine Medical, 1894. Chitienden and Gies. Am. Journ. of Phys., i., p. 1. Wild. Lancet, 1899, i., p. 23. Liebreich. Vierteljahrsch. f. ger. Med., 1900, xviii., p. 83. Lange. Arch. f. Hygiene, xl., p. 143. Kilter. Ztschr. f. Hygiene, xxxvii., p. 225. Tunnicliffe and Rosenheim. Journ. of Hygiene, i., p. 168. Vaughan and Veenboer. Amer. Medicine, 1902, Mar. 15th. XXIV. CARBONIC ACID. Carbonic acid is contained in considerable quantity in many thera- peutic preparations, notably in the effervescent cathartics and antacids, and also in many beverages, such as soda water, potash water, cham- pagne and other sparkling wines. In some of these it is formed by the action of an acid such as citric or tartaric acid on carbonates, in others it is liberated in the course of fermentation, while in the artifi- cial aerated waters it is forced into solution under high pressure. The last are therefore simple solutions of carbonic acid, while in the others more powerful agencies cathartic salts or alcohol are contained in addition. Carbonic acid has a weak irritating action when applied in quantity ; thus in baths charged with carbonic acid, a slight reddening of the skin has been observed, and some irritation and prickling of denuded surfaces is produced ; a stream of carbonic acid directed against a wound or burn causes considerable heat arid pain. Pure carbonic acid gas causes spasm of the glottis when inhaled, and even when it is much CARBONIC ACID. 581 diluted, some irritation in the respiratory passages may follow at first. Solutions of carbonic acid induce reddening of the mucous membrane of the mouth and stomach, and are very rapidly absorbed, owing to the congestion and increased blood flow in the stomach wall which follows their administration. Much of the carbonic acid is thrown up by eructation, but some of it is absorbed and is excreted by the lungs. The absorbed acid has no effect on the organism, but the slight irrita- tion of the stomach may cause increased appetite and a feeling of well- being. The rapid absorption of the water in which it is dissolved is followed by an augmented secretion of urine, and the carbonic acid waters are therefore used in preference to ordinary waters, where a rapid flushing of the tissues and a profuse secretion of urine is de- sired. In addition, the slight irritation of the mouth and stomach renders them more acceptable than ordinary waters in fever and in other diseases accompanied by intense thirst ; a mixture of milk and aerated water is often very grateful. The presence of carbonic acid in the sparkling wines leads to the rapid absorption of the alcohol also, and this action on the stomach may explain their being more ex- hilarating than other wines containing an equal amount of alcohol. The slight irritant effect of carbonic acid in the stomach has proved of benefit in some forms of gastric catarrh, such as that following alcoholic excess. Carbonic acid waters are also useful in the vomiting of pregnancy and in seasickness. The prolonged application of carbonic acid to the mucous mem- branes leads to local anaesthesia, and numbing of the skin is also stated to occur under similar treatment. Carbonic acid is absorbed from all the mucous membranes, from the skin and from the lungs. The gas has no effect after absorption ex- cept when inhaled, however, as when absorbed in any other way it is at once excreted by the lungs, and the amount absorbed never alters appreciably the normal percentage of carbonic acid in the blood. When carbonic acid is inhaled unmixed with oxygen, it induces asphyxia, partly from a specific action which it exerts on the central nervous system, but chiefly from the absence of oxygen. Its effects are therefore very similar to those of any indifferent gas, such as hydrogen or nitrogen, and the symptoms are those of ordinary asphyxia. When, however, carbonic acid is inhaled mixed with a sufficient amount of oxygen, the specific effects of the gas are observed without any asphyxia. The symptoms are those of transient stimulation and subsequent depression of the central nervous system and heart. The first stage is marked by a very short period of psychical exaltation, with deep respirations, a slight rise in the blood- pressure and a moderately slow pulse. Very soon, however, unconscious- ness, loss of the spontaneous movements, and later of the spinal reflexes follow, the respiration becomes somewhat slower and shallower, the pulse continues slow and the heart is weaker. If the inhalation be continued the respiration fails, the heart continuing to beat for a short time, though weakly. The symptoms of the first stage seem to be due to a direct stimulant action on the cerebrum and on the vagus, vaso-motor and respiratory centres, while the second stage resembles that induced by the ordinary anaesthetics, and is evidently caused by depression of the central nervous system and of the heart muscle. In fact a mixture of carbonic acid and air has been used as 582 INORGANIC SALTS, ACIDS AND BASES. an anaesthetic in one or two surgical operations. Death from carbonic acic poisoning is not preceded by convulsions, those observed in ordinary as phyxia being due to the absence of oxygen, and not to the excess of car bonic acid ; it is still undecided by which of these factors the increased per istalsis seen in suffocation is caused. In well diluted vapor the symptom of exaltation alone are observed, no anaesthesia following. Carbonic acid in excess acts as a poison to other organs besides the centra nervous system and the heart, although this effect is not seen in mammals Prog's muscle loses its irritability rapidly, the ciliated epithelium cease movement, and the motor nerves, after a short period of increased excita bility, are paralyzed by exposure to an atmosphere of carbonic acid. Th blood assumes the venous color when shaken with the gas, and prolongei contact produces acid hsematin, as does any other acid. Carbonic acid probably acts as a general poison to the protoplasm in mam mals, apart from the effects on the central nervous system, for the combustio: in the tissues is lessened to an extraordinary degree, as is evidenced by th very small amount of oxygen absorbed. Compressed carbonic acid gas absorbs much heat in expanding, and stream of it directed against the skin induces intense cold and might there fore be used to induce local anesthesia. (See Ether, page 182.) The inhalation of diluted carbonic acid has been recommended in variou pulmonary affections, such as phthisis and bronchitis, but is of very doubl fill benefit. Mineral waters containing large quantities of carbonic acid in solution ar often recommended as baths in various chronic diseases, such as rheumatism The effects may be due to the carbonic acid in part, but these waters als< contain salts in solution. BIBLIOGRAPHY. P. Bert. Lemons sur la Respiration. Paris, 1870. Quincke. Arch. f. exp. Path. u. Pharm., vii., p. 101. Eunge. Ibid., x., p. 332. Friedldnder u. Herter. Zts. f. phys. Chem., ii., p. 99. Loewy. Pfliiger's Arch., xlvii., p. 601. Rothschild. Beitr. z. klin. Chir., xxxv., p. 281. XXV. CHLORINE AND BROMINE. Chlorine and bromine resemble each other closely in the effect which they induce in all forms of living matter. These may be ex plained in part by their replacing hydrogen in its combinations in th proteids and forming hydrochloric or hydrobromic acid with the hydro gen set free, in part by their combining with the hydrogen of wate and thus liberating nascent oxygen, which then acts on the tissues The latter process is believed to account for the fact that chlorine is much more powerful disinfectant in moist air than in dry. In th higher organisms all of these reactions probably occur together. Action. Chlorine and bromine are general protoplasm poisons thus 3 parts of chlorine in 1,000 parts of moist air are sufficient t destroy the spores of most bacteria in the course of three hours, an< the infusoria and the higher plants have been shown to be equall; susceptible to the influence of the gas. Even smaller quantities 01 bromine are disinfectant. In the higher animals and in man chlorine and bromine act a irritants. Thus chlorine water (a saturated solution of chlorine ii CHLORINE AND BROMINE. 583 Water) induces irritation and redness of the skin, and even blistering, when the gas is prevented from escaping, Bromine also causes very painful blistering, the fumes penetrating more deeply into the tissues than the non-volatile irritants, and causing more widespread irritation. Bromine or chlorine water, when swallowed, elicits intense inflamma- tion and corrosion of the mouth, throat and stomach, with collapse and all the ordinary effects of gastric irritation. Air containing even a very small proportion of chlorine irritates the eyes, nose, larynx and the deeper respiratory passages, the bronchi and lungs seeming more susceptible than the rest of the tract, for bronchitis, pulmonary con- gestion and haemorrhages, coughing and pain in the thorax are induced by quantities that cause little or no irritation of the mouth and nose. Lehmann found that one volume of chlorine or bromine vapor in one million parts of air cause some irritation, but no serious results, but that ten volumes in the same amount of air inhaled for some time, cause haemorrhage and inflammation of the lungs, severe bronchitis and other similar effects. After fatal poisoning from the inhalation of bromine, he observed marked irritation of the gastric mucous mem- brane, while this symptom was absent after chlorine. Another point in which bromine differs from chlorine is in its powerful action on the hair, which is rendered soft and gelatinous, and eventually removed entirely by exposure for some time to the vapor. These symptoms of chlorine and bromine poisoning are caused by their local action only, and are so severe that they might conceal those induced by the effects of the halogens after absorption. The greater proportion of the poisons is undoubtedly changed to hydrochloric and hydrobromic acids, and these again to chlorides and bromides in the course of absorption. But it seems possible that some may form proteid compounds in the body (as happens in ths test-tube), and that these may have some action. As a mat- ter of fact both chlorine and bromine are stated to have a narcotic effect on the brain quite apart from their local effects, but nothing further is known of their action in the tissues. Attention has been drawn to a number of cases in which symptoms arose in workmen in chemical factories where chlorine is lib- erated by electrolysis, or more rarely in others where hydrochloric acid is formed in large quantities. The most marked symptom is an affection of the sebaceous glands, from which the condition receives its name of chlorine acne, but this often induces headache, sleeplessness, loss of appetite, and ansemia. No satis- factory explanation of the symptoms has been given, nor is it known whether the chlorine or some unknown body is the cause (Lehmann, Jacquet). PREPARATIONS. Liquor Chlori Compositus (U. S. P.), chlorine water, contains at least 4 parts of the gas in 1,000 parts of water. It is a clear, greenish liquid with the suf- focating odor of chlorine and is liable to form hydrochloric acid, especially when exposed to the air and sunlight. It ought therefore to be freshly prepared when the full strength is required. Calx Chlorinata (U. S. P., B. P.), chlorinated lime, bleaching powder, some- times erroneously called chloride of lime, is a compound formed by the action of chlorine on lime. It consists of a mixture of calcium hypochlorite (Ca(ClO) a ), calcium chloride (CaCl 2 ), lime and water. The hypochlorite is very unstable and gives off chlorine in air, and especially in the presence of an acid. Strong acids also free the hydrochloric acid of the chloride, and this is decomposed by the hypochlorite into chlorine and water. Chlorinated lime forms a white or 584 INORGANIC SALTS, ACIDS AND EASES. grayish- white powder, with the odor of chlorine. It is only partially soluble in water and must contain not less than 35 per cent, of available chlorine, U. S. P. ; 33 per cent. B. P. Liquor Calcis Chlorinates (B. P.). The solution should yield about 3 per cent, of chlorine. Liquor Sodce Chlorinatce (U. S. P., B. P.), so r ution of chlorinated soda, Labar- raque's solution or Javelle's solution, is formed from chlorinated lime and con- tains hypochlorite of soda (NaCIO) and chloride of soda. Like the correspond- ing lime salt, it has the odor of chlorine and bleaches vegetable colors. It must contain at least 2. 6 per cent, by weight of available chlorine, U. S. P. ; 2. 5 per cent., B. P. 10-20 mins. Bromum (U. S. P.), bromine, '* heavy, brownish-red liquid evolving a yel- low-red, very irritant vapor. Chlorine was formerly used internally in infectious disease, but this has been entirely abandoned, since it has been recognized that it is much more poisonous to the higher animals than to the micro-organ- isms. The inhalation of chlorine in phthisis has also fallen into dis- use for the same reason. Chlorine water and the solution of chlori- nated soda are still occasionally used as antiseptic, deodorant solutions in the treatment of foul sores, and, more rarely, to disinfect the hands before operation ; both preparations are very irritant, however. Chlo- rine water much diluted has been used as a gargle, as a vaginal injec- tion and for other similar purposes. The chlorine preparations are chiefly used to disinfect fseces, urinals and to a less extent rooms and houses ; for this purpose chlorinated lime is the most suitable, especially wheu acid is added to it in excess. The room ought to be hermetically sealed, and the fumes are of no value as disinfectants unless they are present in such quantity as to render the air quite irrespirable. They have the disadvantage that they bleach most of the colors used in dyeing, and fail to penetrate in sufficient quantity into the clothing, which they also corrode to some extent. Chlorinated lime exposed in the sick-room merely serves as a deodorant, and has no disinfectant value, but has the disadvantage of giving a false feeling of security like other similar measures. Chlorine seems inferior to sulphurous acid anhydride, and still more so to formalin as a disinfectant, not from its being weaker in action, but because it is more difficult to apply in sufficient quantity. Chlo- rinated lime can, however, be applied in urinals and closets, where both these disinfectants are unavailable. Here it acts again as a de- odorant, while its disinfectant value is smaller. Bromine is also powerfully disinfectant, but has not been used prac- tically for this purpose in recent years. It is occasionally employed as a corrosive, e. g., in disease of the os uteri. In Poisoning with chlorine taken by the mouth, alkalies are advised with the view of neutralizing the acid formed, and narcotics may be necessary for the pain. In cases of poisoning by inhalation, steam may be inhaled to lessen the irritation, and ammonia has been advised, but is itself irritant. In corrosion of the skin with bromine, one half per cent, carbolic acid has been applied with success, it is said, the OXYGEN. 585 bromine being precipitated as bromphenol. Vapor of carbolic acid has also been inhaled in bromine irritation of the nose and throat. BIBLIOGRAPHY. Binz, Arch. f. exp. Path. u. Pharm., xxxiv., p. 194. Lehmann. Arch. f. Hygiene, vii., p. 231 ; xxxiv., p. 308. Fischer u. Proskauer. Mittheil. a. d. Gesundheitsamt, ii., p. 228. Cash. Keports of Brit. Local Gov. Board, 1886. Lehmann. Arch. f. Hygiene, xlvi., p. 322. Jacquet. Semaine medicale, Dec. 31, 1902. XXVI. OXYGEN. Ever since the discovery of the relation of oxygen to the respiration, at- tempts have been made to use it in therapeutics, by inhaling the gas pure or mixed with air, or by spending a certain time each day in chambers of com- pressed air. It was expected that by these means a larger amount of oxygen would be absorbed, and a more active combustion in the tissues would be induced. The absorption of oxygen by the lungs does not depend on the partial pressure of the oxygen, however, but on its affinity for the reduced haemoglobin of the corpuscles. It is true that the oxygen dissolved in the plasma is increased by a great rise in the barometric pressure, or by inhaling pure oxygen, but this dissolved oxygen is trifling in amount com- pared with that in combination with the haemoglobin. Under ordinary con- ditions, then, the air is sufficient to oxidize almost all the reduced haemo- globin passing through the lungs, and oxygen lessens but slightly the small proportion that escapes by the pulmonary veins unoxidized. As far as the tissues are concerned, the oxidation is of course the same whether the oxy- hsemoglobin carried to them by the blood was formed in a pure atmosphere of oxygen or in air, of which it comprises only about 20 per cent. The slight increase in the oxyhaemoglobin of the blood has no appreciable effect, as more oxygen is offered to the tissues normally than they can assimilate. It is therefore inconceivable that the very slight increase in the quantity of oxygen in the blood can have any effect on the oxidation in the tissues under ordinary conditions. But if the gas be inhaled under high pressure the aug- mented tension in the blood may induce some symptoms, and this is, according to Smith, the explanation of a tendency to tetanic convulsions which he found developed in animals under these circumstances ; hilarity and some other nerv- ous effects are said to have been induced in man in some instances, and these may also be interpreted as the results of the high oxygen tension in the blood, if they were not the products of fancy and suggestion. Oxygen inhalation is therefore incapable of increasing the oxidation in the tissues, or in fact of modi- fying in any way the metabolism, and experience has shown it to be valueless in such constitutional diseases as diabetes and gout, in which, moreover, it has been demonstrated that there is no deficiency in the oxygen of the blood. The further question arises whether oxygen inhalation is likely to be of benefit in the cyanosis due to severe cardiac or pulmonary disease. Improve- ment is very often observed clinically, the skin losing its dark color, and the respiration and heart becoming less rapid and labored as soon as the inhala- tion is commenced, and alarming symptoms returning when it is stopped. This may be explained by the larger amount of oxygen dissolved in the plasma ; when air is breathed, the plasma contains only about 0.6 per cent, of oxygen in simple solution, but when oxygen is inhaled the percentage may rise to 3 per cent, and this may reinforce the oxygen carried by the haemoglobin. In cases in which only a small quantity of blood is passed through the lungs owing to circulatory disorder or where the aerating surface 586 INORGANIC SALTS, ACIDS AND BASES. of the lungs is diminished by exudation, this small supplementary supply of oxygen may be of importance. Again the air actually inspired does not pass directly into the alveoli, but diffuses from the wider air passages into the narrower ones and then reaches the absorbent surfaces. Pure oxygen diffuses more rapidly and in larger quantity into the alveoli than when it is mixed with nitrogen, and it is therefore conceivable that when the movement of the air in the air passages is insufficient, oxygen may give relief by diffusing in larger quantity into the alveoli. Insufficient movement of the air currents may be due to obstruction of the respiratory tract, as in asthma or severe bronchitis, or to slow and shallow breathing from depression of the centre. Accordingly, the inhalation of oxygen is said to be followed by relief in some cases of asthma and bronchitis, and it has been recommended in nar- cotic poisoning. When the haemoglobin of the blood is so altered as to be incapable of transporting oxygen to the tissues, as in cases of poisoning with carbon mon- oxide, nitrites, chlorates, nitrobenzol, etc., oxygen inhalation is indicated, for it has been shown by Haldane and others that the plasma dissolves enough oxygen to maintain life when that supplied by the blood corpuscles is insuf- ficient. The inhalation has to be continued until the symptoms of deficient aeration have disappeared. Many microbes are killed or at any rate much retarded in their growth when freely exposed to the air, and attempts have been made to treat pul- monary phthisis by oxygen inhalation. The results have been less disas- trous than those of some of the other treatments by inhalation, but no dis- tinct benefit has accrued, and in some cases haemoptysis has been induced by it from some unexplained cause. Smith has recently found that the in- halation of oxygen under some pressure causes irritation, congestion and consolidation of the lungs in mice and birds. Oxygen is inhaled through a mask connected with a large container which is filled from a tank of the compressed gas. Very often the oxygen may be diluted with air and for this purpose a small opening may be made in the mask. Ozone, or active oxygen (O 3 ), is a much more powerful oxidizing body than ordinary oxygen, but is more easily reduced than peroxide of hydrogen. It has a curious phosphorous odor and is somewhat irritant to the respiratory membranes, but it is almost always accompanied by nitrogen oxides, and some of the properties which have been ascribed to ozone may be due to these impurities. It is rapidly decomposed by living matter, and it seems very improbable that it can be absorbed into the blood ; yet Binz and Schulz believe that ozone induces narcosis in dogs, rabbits and kittens, and Schulz found in experiments in which ozone was inhaled repeatedly for long periods that it induced vomiting and dyspnoea, bronchitis, oedema and blood- extravasation in the lungs ; conjunctivitis also occurred in some experiments. Schulz ascribes these symptoms to the ozone, but they may be due in part at any rate to the impurities, or perhaps to oxygen. Ozone has undoubtedly antiseptic properties, but these are only apparent when air contains 13.5 mg. or more per litre. Even this disinfects only the air itself and the surfaces of objects, as the ozone loses its oxidizing properties when- ever it comes in contact with organic matter and therefore fails to penetrate. It has recently been advocated to disinfect drinking water. Ozone inhalation has been recommended in the hope of increasing the oxidation of the tissues, and as an antiseptic in pulmonary phthisis, but its irritant properties preclude its use here, and it has been generally discarded. It was supposed to be formed in turpentine oil on standing, and old turpen- tine oil was therefore recommended in cases of phosphorus poisoning, with the hope that it would tend to oxidize the phosphorus and render it harmless. Recent investigations show, however, that no ozone is formed in turpentine oil, and there is no reason to suppose that the treatment is of benefit. PEROXIDE OF HYDROGEN. 587 Antozon is a mixture of oxygen and peroxide of hydrogen, and many other so-called solutions of ozone contain only small percentages of the peroxide and no ozone proper, as, though the latter is soluble in water, it decomposes very rapidly, only traces of it being found in the solution after 10-15 days. It breaks up into oxygen, and does not form hydrogen peroxide. The ozone of the air has been appealed to, in order to explain and adver- tise the benefits induced by many watering places and forest resorts but it has never been satisfactorily proved that the air in these localities contains more ozone than in other less favored places. The curative agency is gen- erally the change of scene and interests, and the dietary. BIBLIOGRAPHY. Smith. Jour. ofPhysiol., xxii., p. 307; xxiv., p. 19. Haldane, Makgill and Mavrogordato. Jour. ofPhysiol., xxi., p. 160. Michaelis. Verhandl d. Congresses f. inn. Med., 1900, p. 503. Binz. Berl. klin. Woch., 1882 and 1884. Sonntag. Ztschr. f. Hygiene, viii., p. 95. Cash. Keports of Brit. Local Gov. Board, 1885. Schulz. Arch. f. exp. Path. u. Pharm., xxix., p. 364. Hasenfcnopf. Charite-annalen, xxviii., p. 228. Durig. Arch. f. Anat. u. Phys., 1903, Supplem., p. 209. Cowl and Royovin. Ibid., 1904, p. 1. Hill and Madeod. Proc. Roy. Soc., Ixx., p. 455. Bohr and Maar. Skand. Arch. f. Phys., xvi., p. 41. XXVII. PEROXIDE OF HYDROGEN. Hydrogen peroxide or dioxide (H 2 O 2 ) tends to break down into water and oxygen very rapidly in the presence of many substances, which in themselves may be either oxidizing or reducing. Among the bodies which induce this decomposition or catalysis are all forms of living matter, and the peroxide of hydrogen is therefore decomposed when brought in contact with the tissues, the oxygen thus liberated in a nascent condition tending to oxidize its surroundings ; the chief effects of this liquid are therefore due to its oxidizing properties. It is generally met with in dilute solution in water, and in this form alone is used in medicine. Brought in contact with the skin, peroxide of hydrogen solution is decomposed, and numerous bubbles of oxygen are formed, 1 but this decomposition proceeds much more rapidly when it is applied to denuded surfaces or to mucous membranes. The oxygen is formed in such quantity that some irritation may follow, and thus dogs often vomit when it is administered in quantity by the mouth. When it is injected subcutaneously, a large amount of oxygen is formed in the subcutaneous tissues, but some of the peroxide escapes decomposition and is absorbed into the blood. Here the decomposi- tion proceeds more violently, the red blood cells having a strong cata- lytic action, and the oxygen set free may cause emboli and lead to sudden death. The formation of emboli is seen most frequently in the rabbit, but was in all probability the cause of death in one case of fatal poisoning in man, in which a solution of hydrogen peroxide had been used to wash out the pleural cavity. 2 Emboli are not formed in 1 A concentrated solution is said to corrode the skin, leaving a white eschar. 2 In several other instances hemiplegia has been observed, apparently from embolism of the cerebral arteries. 588 INORGANIC SALTS, ACIDS AND BASES. the dog on hypodermic injection, nor in either dogs or rabbits poisoned by the stomach in the latter case probably because the liquid is more slowly absorbed and is almost entirely decomposed in the mucous membrane. Even in the blood and tissues the whole of the peroxide is not decomposed, for several observers have found traces of it ex- creted in the urine. Injected intravenously in either dogs or rabbits the peroxide is rap- idly decomposed in the blood, and forms emboli which prove immedi- ately fatal by stopping the circulation through the lungs, heart and brain. The action of hydrogen peroxide, then, apart from its local effects is ex- plained by its obstructing the blood vessels mechanically. Colasanti has stated recently that in addition it forms methsemoglobin in dogs and thus leads to a marked decrease in the metabolism from the non-aeration of the tissues, but his statement requires further confirmation. The catalytic decomposition of the peroxide is not necessarily asso- ciated with the life of the tissues, for it occurs also in excised organs and in drawn blood. In fact, it was formerly supposed that it took place only in the blood outside the tissues, and that the circulating blood had no effect on it, but this has been shown to be erroneous. The different organs vary considerably in their catalytic power, the red blood cells and the liver cells being the most active, and it has been stated that this action of the tissue cells is closely associated with the presence of nucleoproteids (Gottstein, Spitzer) ; but Loew has shown that it is due to the presence of a widely distributed ferment (catalase) in most instances. The catalysis of hydrogen peroxide occurs in the lower forms of life as well as in the higher. Thus germinating seeds, yeasts, infusoria and the microbes all free oxygen from the solution, and in fact, a rough estimate of the number of microbes in water may be formed from the amount of oxygen given off by it on the addition of the per- oxide (Gottstein)o This decomposition is fatal to most of these lower forms, presumably from the nascent oxygen, and peroxide of hydrogen is therefore a powerful disinfectant, a three per cent, solution proving as strongly bactericidal as a one per mille solution of corrosive subli- mate ; but when the microbes are contained in a medium with much organic substance, as in wounds, the bactericidal action is very much reduced. In recent years, attention has been drawn to other bodies analogous to hydrogen peroxide, some of which possess powerful microbicidal properties. The peroxide is represented by the structural formula H O O H and one of the hydrogens may be replaced by benzoyl or acetyl, forming C 6 H 5 CO O OH (benzo-peracid) or CH 3 CO OOH (aceto-peracid). These have been shown to be much more powerful germicides than hydrogen peroxide, while they give off oxygen less readily ; in fact they are comparable only to corrosive sublimate in their destructive effect on microorganisms and even sur- PEROXIDE OF HYDROGEN. 589 pass it in favorable conditions. This suggests that the disinfectant action of this group is not really due to its liberating oxygen only, otherwise the activity of these peracids would be less than that of the peroxide as they part with their oxygen less readily. It is possible, however, that the difference really arises from the way in which the oxygen is liberated ; for example, the peracids may penetrate the microbes and free oxygen in their interior, while the peroxide is re- duced before it passes through the cell-wall. The peracids are pre- pared with difficulty and are very unstable bodies, so that it is unlikely that they will prove of value in practical medicine. But they are formed when the aqueous solutions of some more readily available substances are allowed to stand for some time. In these both the hy- drogen atoms of hydrogen peroxide are replaced by organic radicles forming organic peroxides such as diacetyl peroxide (CH 3 CO O O COCH 3 ) and benzoyl-acetyl-peroxide (C 6 H 5 CO O 6 COCH 3 ), On dissolving these in water, the peracids are formed and the solutions are very powerful disinfectants which have been suggested for surgical use and also as intestinal disinfectants ; practical clinical experience alone can decide whether they possess that value which the results in the laboratory seem to indicate. PREPARATION. Aqua Hydrogenii Dioxidi (U. S. P.), Liquor Hydrogenii Peroxidi (B. P.), solution of hydrogen dioxide or peroxide, contains about 3 per cent, by weight of the pure dioxide. Each volume of this solution is capable of set- ting free 9-11 volumes of oxygen when completely decomposed. Some acid is added to the peroxide solution in order to retard its decomposition, but it gradually changes when kept, so that only freshly prepared solutions are of full strength. The solution is colorless and odorless, but has an acid taste from the added acid, and the oxygen freed in the mouth gives a curious sen- sation and forms a froth. Therapeutic Uses. Hydrogen dioxide is used locally as a disinfect- ant solution in suppuration, diphtheria and urethral infection. In pus cavities the oxygen is freed with great rapidity, and the pus-corpuscles are said to be disintegrated. The catalysis is due in part to these cor- puscles, in part to the microbes, and the extent of the suppuration may be estimated from the amount of effervescence. Peroxide solu- tions differ from most other disinfectants in the short duration of the action, which passes off as soon as all the oxygen is liberated. In ad- dition to its microbicidal action proper, this agent loosens and destroys masses of infected material by the mechanical effect of the liberation of the gas, and the wound or cavity is thus cleaned by it more per- fectly than by washing with ordinary antiseptic solutions. The solu- tion has been recommended for use in ophthalmic practice, and for this purpose may be diluted one half. BIBLIOGRAPHY. Gutimann. Virchow's Arch., Ixxiii., p. 23 ; Ixxv., p. 255. Schwerin. Ibid., Ixxiii., p. 37. Altehoefer. Centralbl. f. Bacteriol., viii., 1890, p. 129. 590 INORGANIC SALTS, ACIDS AND BASES. Pane. London Medical Kecord, 1891. Colasanti and Brugnola. Arch. Ital. de Biol., xxv., p. 228. Goltstein. Virchow's Arch., cxxxiii., p. 295. Spitzer. Pfliiger's Arch., Ixvii., p. 615. Honsell. Beitrage z. klein. Chir., xxvii., p. 127. Losw. U. S. Depart, of Agriculture Rep., No. 68. Novy and Freer. Journ. of Exp. Med., vi. (Peracids. ) Other Oxidizing Disinfectants. Other oxidizing bodies have been used as antiseptics and disinfect- ants. Thus Calcium Peroxide or Gorit has been recommended as a gastric and intestinal disinfectant for children in doses of 0.2-0.6 G. in milk. Zinc peroxide and magnesium peroxide have also been sug- gested, the former for external, the latter for internal use. Similarly the Persulphates of potassium and sodium (Na 2 S 2 O 8 ), per- sodine, possess strong oxidizing properties from their liberating oxygen in contact with organic matter. They are only feebly poisonous but have not been extensively used as yet. Some older and better known disinfectants also owe their powers to liberated oxygen, and among these that most largely employed is the Permanganate of Potassium. When a solution of this salt comes in contact with organic matter, such as albumin, the permanganate at once parts with some of its oxygen, which attaches itself to the albumin. Permanganate is thus poisonous to protoplasm, not through the presence of the whole mole- cule, but in consequence of the oxidation of the proteids. As soon as the permanganate is reduced, it of course loses this action, so that the oxidizing effect is limited to the skin and the surface of the mucous membranes. Concentrated solutions irritate, and even corrode the skin, and induce gastro-enteritis when swallowed. Permanganate solutions are disinfectants of considerable power, owing to their oxidizing and thus destroying bacteria. They fail to penetrate deeply in an active form, and this renders them of less value than many other disinfect- ants, except in very superficial infection. PREPARATIONS. Potassii Permanganas (U. S. P., B. P.) (KMnO 4 ) forms slender crystals of a dark purple color and a sweetish, afterwards disagreeable and astringent taste, soluble in sixteen parts of water, reduced by alcohol and other or- ganic bodies. 0.05-0.2 G. (1-3 grs.), in pills made up with kaolin. Liquor Potassii Permanganatis (B. P.), a 1 per cent, solution in water. 2-4 fl. drs. Therapeutic Uses. The permanganate has been used internally in amenorrhcea and chlorosis. Externally it is used for its disinfectant and deodorant action, as an application to gangrenous ulcers, cancerous sores, diphtheria, and gon- orrhoea. In dilute solution it may be used as a gargle and mouth wash (1 per cent.), to disinfect the hands (1-3 per cent.), which it stains brown, and for other similar purposes. It has recently been recommended in poisoning with phosphorus, prussic acid, morphine and other alkaloids, on the theory that these PHOSPHORUS. 591 poisons are oxidized by it in the stomach, and thus rendered harm- less. For this purpose it is given in J per cent, solution. It may be questioned whether much permanganate reaches the stomach unreduced, and the method is certainly less reliable than the stomach tube. Only the poison actually in the stomach is destroyed, permanganate having, of course, no effect upon that absorbed into the blood. In snakebite, permanganate has been advised, and it undoubtedly has some action on the poison when it comes in contact with it, and may therefore be used to wash the wound and also to inject around it ; it has no effect upon the poison already absorbed. Condy's Fluid is a strong solution of impure permanganate, which is of use to disinfect and deodorize urinals and faeces, but must be poured on them, and cannot be employed to disinfect rooms. Some of the caustics owe part of their action to the oxygen liber- ated when they come in contact with organic matter. Thus Chromic Acid destroys tissue in part through its acidity but this is reinforced by its oxidizing powers. XXVIII. PHOSPHORUS. In the early part of last century phosphorus played a very important role in therapeutics, and, in fact, was regarded almost as a panacea, but at present its use is much more restricted, and some doubt is en- tertained as to its possessing any therapeutic value whatever. At the same time it has been the subject of much and laborious investiga- tion, partly because it has frequently given rise to poisoning, and partly because the study of its effects has thrown much light on some physi- ological and pathological processes. It differs from most poisons in acting for the most part on certain phases of the animal metabolism, and in having comparatively little direct action at the point of appli- cation, or, indeed, upon any single organ. Phosphorus is absorbed with difficulty, because it is very insoluble in water and the body fluids and is only slowly volatilized at ordinary body temperature. Large masses of phosphorus may thus pass through the alimentary canal without serious effects, because they fail to be dissolved and absorbed. But when it is taken in a finely divided con- dition or in solution in oil, it gives rise to symptoms in very small quantity, and has been found to induce fatal poisoning in man in doses of 0.05-0.1 G. (1-2 grs.). 1 In these conditions it is absorbed partly as vapor, partly in solution in water, which dissolves only traces how- ever, and probably chiefly in solution in the fats and oils, in which it is much more soluble. Phosphorus vapor is also absorbed by the lungs, and the symptoms of chronic poisoning in match factories are believed to arise in this way. It does not seem to be taken up from the skin, and has in fact little effect unless when rubbed on it, when it ignites and gives rise to severe burns ; phosphorus burns do not cause 1 Phosphorus is often used in suicide, generally in the form of rat poison or of match heads. Each phosphorus match is estimated to carry 3-5 mg. of phosphorus, so that 15-20 match heads are sufficient to induce fatal poisoning. 592 INORGANIC SALTS, ACIDS AND BASES. phosphorus poisoning, however, as is sometimes stated. The red amorphous phosphorus is much less poisonous than the ordinary yel- low form, because it is less soluble and also less volatile, and conse- quently fails to be absorbed. Phosphorus exists in the blood as such, and the eifects on the tissues are unquestionably due to the element itself, and not to the oxygen or hydrogen compounds, as has been supposed. Some phosphuretted hydrogen (PH 3 ) may be formed in the bowel, but is comparatively unimportant, the great mass of the phosphorus being absorbed un- changed. As soon as it is oxidized, phosphorus loses its specific ac- tion, all of the acids being comparatively harmless. Phosphorus has been detected in the blood, and, it is said, in some of the excretions. It is devoid of action on albumins in solution, and has no immediate irritant eifects, such as are seen in poisoning with the heavy metals. Symptoms. When a poisonous dose of phosphorus is swallowed, no effects are elicited as a general rule for several hours. The first symp- toms are pain and discomfort in the region of the stomach, nausea and eructation of the vapor with its characteristic garlic odor, and then vomiting, the contents of the stomach having the same odor, and being phosphorescent in the dark. Later, bile may be vomited, and some diarrhoea may set in, although this is not a common symptom. The nausea and vomiting often continue without further symptoms for several days, but frequently disappear, and the patient apparently recovers, particularly if the dose has been small, or if most of it has been removed by vomiting or by washing out the stomach. In the course of a few days, however, the symptoms recur, and are generally accompanied by some jaundice ; the pain extends from the stomach to the liver, and soon to the whole of the abdomen. The vomited matter no longer contains phosphorus, but may be bloody. The patient com- plains of general weakness and faintness ; the pulse is weak, the liver ex- tends far below the ribs, and the urine shows characteristic changes (see page 602); haemorrhages occur from the nose, bowel, uterus, and under the skin, and eventually a condition of collapse and fatal coma follow. Convulsions and delirium have been observed in a considerable pro- portion of cases towards the termination of the intoxication. Death may occur, however, in the first stage or early in the second, before complete exhaustion is reached, and in these cases would seem to be best explained by the direct action of the poison on the heart. If only a small quantity be swallowed or if active therapeutic measures be taken early, the patient may recover without any secondary symptoms, and even when these have followed, the prognosis is not hopeless, for the symptoms slowly disappear in a certain proportion of cases. Exposure to the fumes of phosphorus has long been known to give rise to periostitis and necrosis of the lower jaw. The disease begins from a carious tooth or from some lesion of the gum, and may involve most of the jaw, which becomes swollen and painful and eventually evacuates large quantities of pus with pieces of dead bone. This ne- crosis was formerly frequent in match factories, but has become rarer PHOSPHORUS. 593 since amorphous phosphorus has been substituted for the yellow form, 1 and since greater attention has been paid to the ventilation of the fac- tories and to the condition of the teeth of the employees. Magitot has recently advanced the opinion that exposure to phosphorus fumes gives rise to a mild chronic form of poisoning, quite aside from the necrosis, which is comparatively rare. The symptoms are cachexia, slight jaundice, anaemia, and abuminuria, and in more advanced cases chronic enteritis and diarrhoea, bronchitis, and a curious fragility of the bones. Action : Fatty Degeneration. A very striking feature in phosphorus poisoning, and one that was early recognized in its history, is the ap- pearance of numerous fat globules in the cells of many organs, notably in those of the liver, kidney, gastric and intestinal glands, and in the muscle fibres of the heart, stomach, intestine, smaller arteries and often of the skeletal muscles. The question has been raised whether this fat is formed by the degeneration of the protoplasm of the cells in which it is found, or whether it is not transported from other parts of the body and only deposited in these cells, the school of Yoit maintaining the former view, while Pfliiger and his pupils uphold the latter. The advantage at present seems to lie with Pfliiger, who has shown that the total fat of the body is not increased by phosphorus, although this has been met by Lindemann's explanation that a certain amount of fat is destroyed during the intoxication, and that if more fat were not formed from the proteids through the action of the poison, there would be found a marked deficiency at death. A strong argument for Pfliiger's view is adduced by Rosenberg, who found that when an animal has been fed on foreign fats (e. g., a dog upon mutton suet) and is then poisoned with phosphorus, the fat found in the liver cells is that characteristic of the food and not that of the poisoned animal as might be expected if it were derived from the proteids. The question cannot yet be said to be determined, although the burden of proof certainly seems to rest on the defenders of the earlier view that the fat arose from the degenerated proteids of the cells in which it is found. The fatty degeneration or infiltration sets in only after some time, and, in fact, accompanies the secondary symptoms for the most part, although the cells of the stomach and upper part of the intestine suffer sooner, and the beginning of this process is probably the cause of the early vomiting. In phosphorus poisoning, as in other instances of fatty degeneration, the process commences in cloudy swelling of the cells followed by the appearance of granules, which soon develop into fat globules. Even- tually the degenerated cells break up into detritus. Another feature in phosphorus poisoning, which is, however, better seen after repeated small doses than after a single large one, is the Proliferation of the Interstitial Connective Tissue of the stomach, liver lr The phosphorous sesquisulphide (P 4 S 3 ), recently introduced in match factories, seems to be even safer than red phosphorus, for though minute quantities of the ele- ment are released from it in the tissues, these are too small to induce any symptoms. 38 594 INORGANIC SALTS, ACIDS AND BASES. and kidney, which finally induces typical cirrhosis of these organs. It was formerly supposed that this indicated a specific irritant action of the phosphorus vapor on the connective tissue, but many pathologists now regard this proliferation as a secondary result of the necrosis of the parenchyma cells. In animals poisoned by the prolonged adminis- tration of small quantities of phosphorus, the ordinary effects of hepatic and renal cirrhosis have been induced, such as dropsy, anaemia and cachexia. Besides the cells which have undergone fatty degeneration, the liver often contains numerous microscopic areas of necrotic tissue and in other parts actively dividing parenchymatous cells. When very minute quantities of phosphorus are administered to animals, no poisoning results, but according to Wegner a specific action on the Bones is induced, especially in young animals, in which the bones are still growing. Thus, in young rabbits, quantities of J0J- mg. given for several weeks are found to be followed by char- acteristic changes in the growth of the long bones, apparently in- duced by the phosphorus acting as an irritant or stimulant to the bone-forming cells (osteoblasts). Wherever cancellous bone is being formed from cartilage, phosphorus is stated by Wegner to cause the deposit of a layer which resembles the dense bone of the shaft in the normal animal in general appearance and also histologically. This layer of dense bone at the growing point is at first the only change induced, but if the treatment lasts longer, the soft cancellous bone which was deposited before the phosphorus treatment began, is gradually absorbed. The medullary cavity of the bone is thus enlarged, and may, in fact, extend into the epiphyses, which in the normal bone are filled with cancellous tissue, but which now form part of the much lengthened cavity. Eventually the whole of the cancel- lous bone may be absorbed, and a similar process of absorption begins in the bone formed at first under phosphorus, while the dense deposit is pushed further into the remaining cartilage. The development of bone from cartilage is not the only process affected, however, for Wegner states that in the bone deposited from the periosteum a some- what similar change is induced, as is shown by its becoming denser and by the Haversian canals being much contracted in size. In full- grown animals the changes in the bone are much less distinct, but the lamellae of the spongy tissue are said to be thickened by phosphorus treatment, and in the fowl Wegner states that the medullary cavity may be completely obliterated by the deposition of hard bone. Wegner supposes that this effect on bone is due to a specific action on the bone- forming cells, analogous to that which he observed in the connective tissue of the liver. As has been mentioned already, however, the cir- rhosis of the liver in chronic phosphorus poisoning is believed by many not to be due to primary irritation of the interstitial tissue, but to be secondary to the destruction of the parenchymatous cells, so that this analogy is rendered doubtful. Wegner found further that when the calcium salts were withdrawn PHOSPHORUS. 595 from the food of animals treated with phosphorus, the exaggerated ac- tivity of the bone-forming cells continued, but no lime was deposited, so that the bone presented the appearance of rickets. The same re- sult has, however, been obtained by other investigators by the with- drawal of calcium without phosphorus. Kassowitz took up the inves- FIG. 50. A B Section of the head of the femur in calf. A, normal, B, after treatment with minute doses of phosphorus. C, the cap of dense bone at the growing point. (After WEGNKR. ) tigation some twelve years later, and observed the layer of white dense bone described by Wegner at the edge of the ossifying cartilage, but regards it not as the result of excessive activity of the osteoblasts, but as due to a slower absorption of the calcified cartilage from a less rapid extension of the blood vessels than is normal. With large doses he produced appearances closely resembling those of rickets. Several other investigators have observed changes in the bones after phos- phorus, so that there is good reason to believe that it possesses some specific action on them, although some writers failed to obtain definite results and of those who observed a modification in the growth no two agree in the description of the changes or in their interpretation. This specific action on the bone-forming tissues and particularly on the periosteum has been used by Wegner to explain the necrosis of the jaw in match factories. He supposes that the phosphorus vapor reach- ing the periosteum of the jaw through a carious tooth or some lesion of the gums, excites a mild periostitis, which in turn leads to the for- mation of new layers of bone around the jaw. Necrosis of the bones has not been satisfactorily demonstrated in animals exposed to phos- phorus vapor, although numerous experiments have been performed with the object of studying its development. The view of the latest investigators is that microbial infection is necessary to permit of the changes observed clinically, but that phosphorus induces some change in the bones which predisposes them to infection by the tubercle ba- 596 INORGANIC SALTS, ACIDS AND BASES. cillus and other organisms which induce necrosis. The occurrence of necrosis of the jaw is in fact a strong argument for the correctness of the view that a specific action on bone exists, for under no other poison, even when much more irritant vapor is inhaled, does a similar process occur in man. The exact nature of this action on bone, and its rela- tion to rickets and to osteomalacia must, however, be left for further research to determine. Phosphorus weakens and slows the Heart when it is applied to it directly in the frog, or by intravenous injection in mammals. In many cases of acute poisoning in man, however, the heart does not seem to be seriously affected until very late, and this is particularly the case when comparatively small quantities have been absorbed. In those cases in which large amounts are swallowed in solution or in fine division, and in which death occurs before any secondary symp- toms have been developed, the fatal issue is generally ascribed to the cardiac action. This direct action on the heart must be distinguished from the fatty degeneration of the cardiac muscle, which is seen in the later stages of poisoning, for no degeneration of the heart, and, in fact, no pathological changes whatever, may be found in those rapidly fatal cases. Phosphorus acts on the heart muscle directly, and does not seem to affect the regulating nerves in any way. According to Pal, the blood-pressure is lowered in some cases not by cardiac action, but by the dilation of the vessels. The Blood is but little changed outside the body by phosphorus, for though Araki states that the haemoglobin parts with oxygen more slowly than usual, the difference is trifling. In many cases of fatal poisoning, the blood is found not to clot so readily as usual, and some- times to remain fluid for forty-eight hours or more. According to Corin and Ansiaux and Jacoby this occurs only in cases in which the patients live for several days, and is not a direct effect of the poison, but is due to the changes in the intestine and liver, which lessen or entirely destroy the fibrinogen. Jacoby states that the blood not only fails to clot but is capable of redissolving fibrin and attributes this to the presence of the autolytic ferment of the liver. The absence of clotting in the blood may be a factor in the haemor- rhages which are met with among the symptoms of the second stage, but the immediate cause of these is the fatty degeneration of the mus- cular coat of the smaller arteries throughout the body. These changes in the blood vessels may perhaps explain the oedema of the retina, which is seen in animals poisoned with phosphorus, though these have also been attributed to some change in the blood. Occasionally gan- grene of the extremities has been observed in phosphorus poisoning, probably owing to the changes in the vessel walls. Small doses of phosphorus generally increase the number of the red- blood cells in man, and even in poisoning a sudden or gradual increase in these may occur, along with a diminution of the leucocytes. The haemoglobin is not correspondingly augmented, however. In the lower animals the effect on the blood cells varies a great deal ; in the dog an PHOSPHORUS. 597 unusual number of red blood cells appears to be destroyed ; in the rab- bit no distinct alteration in the number of the red cells but some leuco- cytosis has been observed, while in fowls an increase in the leucocytes accompanies a marked destruction of the red cells ; in the frog the number of red cells is not reduced. The Bone-marrow in chronic poisoning is at first hypera3mic, the fat cells are atrophied and the leucoblasts are greatly increased ; later a gelatinous degeneration sets in with a decrease in the number of the marrow-cells and a corresponding increase in the connective tissue. The peripheral Nerves and Muscles do not seem to be affected in phosphorus poisoning, except in so far as the latter undergo fatty de- generation. An excised muscle lives almost as long in salt solution containing phosphorus as in the unpoisoned solution. The Central Nervous System is also little changed by phosphorus. The coma and convulsions which appear before death may be due rather to the disordered metabolism than to any direct influence, as is shown by the fact that consciousness is preserved throughout the first stage, and as a general rule until late in the second. The fatty degeneration of the epithelial cells of the Stomach and Intestine explains the abdominal pain, the vomiting and the occasional diarrhoea seen among the secondary symptoms. The earlier phases of this action may be the cause of the vomiting and nausea of the first stage. This degeneration occurs also when phosphorus is injected hypodermically, and is therefore of the same nature as that in the other organs. The cells of the stomach first attacked are those of the glands, and the condition has been termed gastradenitis. The fatty changes in the Liver cause a considerable increase in the area of hepatic dulness, and at the same time induce some pain and tenderness over the organ. The icterus of phosphorus poisoning has been examined by Stadel- mann in dogs. He found that the changes in the bile secretion may be divided into three phases, in the first of which a larger amount of bile pigment is excreted than usual, this denoting an unwonted activity of the liver cells. In the second phase the bile becomes clouded, is less deeply colored and more viscous, and icterus makes its appearance in the skin and conjunctiva. The secretion in this stage seems to be derived largely from the mucous cells of the smaller bile ducts, and contains comparatively little of the excretion of the liver cell proper, In the third phase, which is that of recovery, the bile loses its turbidity and viscosity, and is very dark in color, because the pigment which was deposited in the tissues during the second stage is reabsorbed and excreted in the bile ; the jaundice color of course disappears from the skin as the bile pigment is reabsorbed. The bile salts are also very much reduced in phosphorus poisoning. Stadelmann attributes these changes to the bile capillaries being rendered less pervious, by the en- larged liver cells or the proliferating connective tissue pressing on them and narrowing their lumen. This prevents the bile which is formed by the liver cell from reaching the gall bladder, and the pigment is 598 INORGANIC SALTS, ACIDS AND BASES. therefore absorbed and gives rise to jaundice. The pale viscous fluid which escapes from the ducts in the second stage is probably not true liver secretion, but mucus from the ducts. During recovery, the hepatic cells lessen in size, the pressure on the bile capillaries is relieved and the secretion escapes, while the pigment which was distributed through the tissues is reabsorbed and excreted by the ordinary channel. The jaundice may also be accounted for in part by the destruction of the red cells of the blood and consequent increase of pigment formation in the liver. This view is supported by the fact that in the rabbit, in which the red cells are not decomposed by phosphorus, no icterus is observed, while in the dog, in which some of the cells are destroyed, it is very marked. In man, however, there is no evidence that the red cells are di- minished in number, yet jaundice is one of the commonest symptoms. The bile very often contains albumin in considerable amount, and in the later stages red blood cells may occur in it. In addition to the fatty infiltration of the cells and the changes in the bile, the liver has been shown to undergo a specific alteration in its activity, which is manifested by the presence of large quantities of ammonia, protagon, jccorin, leucin and tyrosin, while less lecithin than usual is present. When the liver of an unpoisoned animal is kept from putrefaction for some time, the tissue is broken down by the ac- tion of an autolytic ferment, and the same constituents are formed in large quantity ; the liver in phosphorus poisoning undergoes the same changes when preserved from putrefaction, but the autolysis progresses much more rapidly. Jacoby therefore infers that phosphorus aug- ments the activity of the autolytic ferment of the liver and thus leads to the presence in the living organ of some products which are absent in the normal one. He regards the disappearance of the fibrinogen of the blood as a further effect of this liver autolysis, for he found that the injection of the autolytic ferment into normal animals prevented coagulation. The fatty degeneration of the Renal Epithelium may account in part for the albuminuria, which is not generally severe, and is not infre- quently absent in cases of poisoning. Fatty casts and even globules of fat are often found in the urine in cases which run a chronic course. Blood and haemoglobin may also appear in it from haemorrhages into the kidney. The other changes in the urine are not referable to the renal disease, but to the modification of the general metabolism of the tissues, the kidneys merely excreting the abnormal products of decom- position which appear in the blood. These abnormalities in the Urine have been examined very often, but some discrepancies are still to be found in the accounts of different authors. The urine itself is often somewhat increased in quantity in the early stages of the intoxication, but afterwards becomes deficient, and towards death complete anuria may be observed. The increased urine is probably due to the increase of the urinary substances in the blood, while the diminution, which may occur early, may be explained by the small quantity of water absorbed from the stomach and intes- PHOSPHORUS. 599 tine, by the degeneration of the secretory cells, or by the failure of the circulation. The nitrogen of the urine varies considerably in different cases. Very often in the first few days after the ingestion of the poison, it is markedly diminished in amount, but this is not due to any specific action of the poison, but to the prolonged nausea and vomiting which prevent the absorption of food ; the nitrogenous excretion thus cor- responds to that during the first few days of starvation. After this, however, a very considerable increase in the nitrogen is observed, even although the patient continues to fast. In the course of starvation a rise in the nitrogen excretion also occurs after some time, but this is never so great as that seen in phosphorus poisoning, so that the poison has generally been credited with a specific action increasing the waste of the nitrogenous tissues. The excretion of urea does not increase in proportion with the total nitrogen, in fact less urea is often excreted than in the first days of the intoxication. But the nitrogen excreted in the form of ammonia is much increased in man and the dog, while it is not altered in the rabbit. This excretion of ammonia suggests the formation of excess of acid in the tissues, 1 and as a matter of fact sar- colactic acid is found in very considerable quantity in the urine in man, the dog and the rabbit in phosphorus poisoning. The increased am- monia of the urine is therefore to be referred, at any rate in part, to the formation of this acid in the tissues, and if fixed alkalies are adminis- tered, the ammonia of the urine falls at once in amount because the alkali neutralizes the sarcolactic acid. The uric acid excreted is often somewhat increased in amount, but on the whole is little altered by phosphorus in man. This perhaps indicates that the nuclei of the cells are less subject to the action of the poison than the cytoplasm, and this is supported by histological examination, for the fat globules are found in the cell body, and not in the nucleus. Some increase in the other nitrogenous constituents of the urine also occurs in phosphorus poisoning, and a number of amido-acids have been identified in it. The best known of these are tyrosin and leucin crystals, which are not always present in the urine, however, although they have been found in the blood in some quantity. Baumann found an increase in the substances of the aromatic series in the urine. Albu- min may be present in small amount, and peptone is sometimes ex- creted. The chlorides of the urine are much reduced in amount, owing to the patient taking little or no food. The phosphates of the urine are often very considerably augmented, but not because of the excretion of phosphorus as phosphates, for the quantity absorbed is too small to cause any appreciable change. The increase in the phosphates is rather to be ascribed to an augmented waste of the tissues, and the sulphates are also excreted in larger quantity for the same reason. When icterus is present, the urine may be dark in color from the 1 See Ammonia, Acids, pp. 551, 555. 600 INORGANIC SALTS, ACIDS AND BASES. bile pigment excreted, and bile acids are also often contained in it. Sarcolactic acid appears in considerable quantity, and is sometimes accompanied by some sugar. Metabolism. The carbonic acid excretion and oxygen absorption by the lungs are generally found to undergo comparatively slight changes in phosphorus poisoning, while all the evidence points to grave de- rangement in the proteid metabolism. Meyer found the alkalinity of the blood reduced through the presence of lactic acid in excess in the tissues, and this has the further effect of increasing the ammonia of the urine ; lactic acid is also found in the stomach along with hydrochloric acid. It is believed to arise from the glycogen of the liver, which is much reduced in amount. This lactic acid formation has been attributed to deficient oxidation in the tissues, which has long been held to be one of the fundamental features of phosphorus poisoning. In addition, the nitrogenous constituents of the body are obviously destroyed more rapidly than usual, for unusually large amounts of nitrogen appear in the urine ; some of this increase may, it is true, arise from the acid formation, and thus indirectly from the deficient oxidation. More recently the great similarity between the results of normal autolysis and of phosphorus poisoning has led several investigators to believe that the essential effect of phosphorus is an acceleration of the autolytic process, and this is supported \>y the results obtained by Jacoby in experiments in which the autolysis of the normal liver was compared with that of the liver obtained from an animal poisoned with phosphorus. Autolysis or destructive metabolism occurs in normal living cells, but in phosphorus poisoning it is supposed to proceed more rapidly, and many of its products are not so completely decomposed as nor- mally, so that intermediate products, such as leucin, tyrosin and other amido-acids, appear in large quantities in the organs and often in the excretions ; lactic acid is similarly a product of autolysis, which fails to be oxidized to carbonic acid as in the normal body. This accel- erated autolysis occurs not only in the liver but also in other organs, although in a less marked degree. It was formerly believed that the fatty degeneration was dependent on lessened oxidation ; l that the fat formed by the decomposition of the proteids could not be oxidized as it is normally, and therefore remained in the cell. But this is not consistent with the view prevail- ing at present, that the accumulation of fat in the liver and other organs is due to its migration from other parts of the body, so that the relation between the two phenomena is not so simple as has been sup- posed. It seems probable that the fatty degeneration is a secondary result of the accelerated autolysis ; according to some writers (Wald- vogel) the fat arises from the proteids in the process of autolysis, but it 1 The lessened oxidation in the tissues was at one time believed to be due to the phosphorus using up the oxygen for its own oxidation, but this is obviously incorrect, for the amount of oxygen required for this would be quite insignificant. Another theory, that phosphorus acts by liberating nascent oxygen in the cells, is based on no sufficient evidence. PHOSPHORUS. 601 seems more plausible to suppose that the cells in the condition of unwonted activity draw upon the fat already present in the tissues and store it in their interior in the form of globules. In view of the curious effect of phosphorus on the tissue change of the vertebrates, its action upon simpler forms possesses some interest. It has been found, however, that yeast, infusoria and bacteria are very little affected by the presence of this poison, and living microbes are found in large numbers on solid pieces of phosphorus. The ferments are also unaffected for the most part, pepsin and pancreatin acting in the presence of phosphorus. Curiously enough, although the oxida- tion is imperfect in animals poisoned with phosphorus, Hauser has found that if phosphorus be added to the blood which is perfused through an excised organ, the oxidation is as rapid as if no poison had been added. He found, however, that some of the synthetic processes of the body were probably retarded by it, for less hippuric acid was formed in a kidney perfused with blood containing phosphorus than in one in which normal blood was used. On the other hand the autolytic activity of the liver is augmented, as has been noted already. The Temperature is often low in the later stages of phosphorus poisoning, but slight fever is also observed in some cases. The Fate of phosphorus in the body is still obscure. It is possible that some of it is oxidized to phosphoric acid, and some phosphorus is said to be excreted by the lungs, although the statement that the breath becomes phosphorescent seems to be extremely improbable. It is also excreted in the urine in some organic combinations, of which nothing is known, though they are said to be volatile. In pregnant animals poisoned with phosphorus, the 'foetus is found to undergo fatty degen- eration, so that the poison would seem to pass through the placenta. Phosphuretted hydrogen (PH 3 ) induces the same symptoms as phos- phorus, when it is given in repeated small quantities. Larger doses are very rapidly fatal and the symptoms differ entirely from those of phosphorus poisoning, consisting of marked dyspnoea, purgation, weak- ness, tremor, and finally violent convulsions and respiratory failure. The oxygen compounds do not seem to have any such effects, and for the most part are harmless except in very large doses. PREPARATIONS. Phosphorus (U. S. P., B. P.), a translucent, nearly colorless solid resembling wax in lustre and consistency. It emits white fumes in the air, which are luminous in the dark, and takes fire spontaneously. The fumes have the odor of garlic, and in dilute solution phosphorus has a harsh, disagreeable taste. It is very little soluble in water, more so in alcohol, and dissolves to about two per cent, in fats and oils. -1 mg. (r&n 3*3 gr.) (B. P. jiiff-sV gr.)- Oleum Phosphoratum (B. P.) is a one per cent, solution in almond oil and ether (1-5 mins.). Phosphorated oil ought to be freshly prepared and kept in tightly stoppered bottles ; solutions of one per cent, tend to lose their strength by evaporation of the phosphorus and by oxidation, when the bottle contains air. It is said to keep better in more dilute solution (one per mille). It is probable that much of the oil dispensed is under one per cent, in strength. Pilulce Phosphori (U. S. P.), each pill contains 0.6 mg. of phosphorus ( T ^ gr.). Pilula Phosphori (B. P.), 2 per cent., 1-2 grs. 602 INORGANIC SALTS, ACIDS AND BASES. Therapeutic Uses. Phosphorus has been recommended in various diseases of the central nervous system and in neuralgia, but it is still questionable whether it is of any real benefit in these. There is more reason to believe in its virtues in bone disease, more especially in rachitis and osteomalacia, for in a number of instances marked im- provement has been observed in these diseases under its use. It is generally given in solution in cod-liver oil, and the benefit may be due in part to the menstruum, but not entirely, for Sternberg observed a relapse in a case of osteomalacia when pure cod-liver oil was substi- tuted for the phosphorated oil. In rickets a solution containing 0.01 G. in 100 c.c. of cod-liver oil is recommended ; 2-4 teaspoonfuls to be given each day. 1 In osteomalacia a one per cent, solution may be prescribed and 1-5 mg. phosphorus taken each day. Rey found the lime excreted in the urine in rickets increased under the treatment with phosphorated cod-liver oil, much less under the oil alone, and not at all under phosphorus alone. He regards this as in- dicating an increased absorption of lime from the food. Other bone diseases, such as caries and ununited fractures, have also been treated with phosphorus occasionally, but the results have not been recorded in sufficient numbers to allow of any statement as to the efficacy of the treatment. Treatment of Phosphorus Poisoning. Phosphorus is comparatively slowly absorbed from the alimentary canal, so that in the early stages an attempt ought to be made to remove it by emetics or the stomach tube, and by purges. Fats and oils must be avoided, as they tend to dissolve the poison and promote its absorption. Phosphorus has been found in the stools three days after its ingestion, and a sharp purge may therefore be of use up to this time. Another method of treatment is that aiming at the oxidation of the phosphorus in the stomach, or at the formation of unabsorbable com- pounds. Turpentine oil was formerly used with the object of oxidizing the phosphorus or of forming some compound with it in the stomach, but this treatment has proved quite valueless (Plavec). Sulphate of copper is recommended in phosphorus poisoning, a large dose being given first as an emetic, and afterwards smaller doses to form an insolu- ble compound, copper phosphide. Permanganate of potassium solu- tion, one per roille, has been recently advised to oxidize the phosphorus, while peroxide of hydrogen solution is of less value. In the secondary stage alkalies are recommended in order to neutralize the excess of sarcolactic acid formed in the tissues. Phosphorus necrosis has to be treated surgically on the same princi- ples as other necroses of bone. 1 This would be equivalent to J-2 mg. of phosphorus daily, but as a matter of fact the phosphorated oil from which the prescription is filled contains much less than one per cent., so that the dose actually taken probably seldom amounts to more than one milligram daily. ARSENIC. 603 BIBLIOGRAPHY. Wegner. Virchow's Arch., Iv., p. 11. Kassou-itz. Ztschr. f. klin. Med., vii., p. 36. Sternberg. Ibid., xxii., p. 265. Stubenrauch. Arch. f. klin. Chir., lix., p. 144 ; Ixi., p. 547. Jacoby. Zeitschr. f. physiol. Chem., xxx., p. 174. Mivau. Stoeltzer. Jahrb. f. Kinderheilkunde, xlvii., p. 153. Rey. Deutsch. med. Woch., 1895, p. 569. Stadelmann. Arch. f. exp. Path. u. Pharm., xxiv., p. 270. Aufrecht. Deutsch. Arch. f. klin. Med., xxiii.. p. 331. Ackermann. Virchow's Arch., cxv., p. 216. Stolnickow. Arch. f. Anat. u. Phys., 1887. Supplement, p. 1. Schidtze. Virchow's Arch., cii., p. 299. Meyer. Arch. f. exp. Path. u. Pharm., xiv., p. 313. Pal Wien. klin. Woch., ix., p. 999. Sehni. Arch. f. Pharmacie, ccxvii., p. 253. Plavec. Arch., f. exp. Path. u. Pharm., xlviii., p. 150 ; Pillager's Arch., civ., p. 1. Miura. Virchow's Arch., xcvi., p. 54. Bauer. Ztschr. f. Biol., vii., p. 63 ; xiv., p. 527. Schultzen u. Riess. Annalen der Charite, xv., p. 1. Fraenkel Berl. klin. Woch., 1878, p. 265 ; Virchow's Arch., Ixvii., p. 278. Falck. Arch. f. exp. Path. u. Pharm., vii., p. 376. Waldvogel. Virchow's Arch., clxxvii., p. 1. Fraenkel u. Rohmann. Ztschr. f. physiol. Chem., iv., p. 439. Leo. Ibid., ix., p. 469. Araki. Ibid., xvii., p. 311 ; xix., p. 422. Munzer. Deutsch. Arch. f. klin. Med., lii., p. 199. Taussig. Arch. f. exp. Path. u. Pharm., xxx., p. 161. Hauser. Ibid., xxxvi., p. 165. Pilzecker. Ztsch. f. physiol. Chem., xli., p. 157. Oorin u. Ansiaux. Vierteljahr. f. ger. Med., 1894, i., pp. 80, 212. Lebert et Wyss. Arch. gen. de MM., 1868, ii., p. 257. Athanasiu. Pfl tiger's Arch., Ixxiv., p. 511. Taylor. Journ. of Exp. Med., iv., p. 399 ; Journ. of Med. Research, ix. Stockman and Charter is. Journ. of Path, and Bact., 1903, p. 205. Thayer and Wolf. Journ. of Med. Research, ix., pp. 191, 216. Santesson. Skand. Arch, f, Phys., xv., pp. 259, 420. Jokote. Arch f. Hygiene, xlix,, p. 275. Rosenfeld. Cong. f. inn. Med., xv., p. 427. Lindemann. Arch. f. exp. Path. u. Pharm., xli., p. 191. Ztschr. f. Biol., xxxix., p. 1. Steinhaus. Ziegler's Beitriige z. path. Anatomie, xxii., p. 466. Monti, Slick, Frdnkel, Zwei/el, Kassowitz. Wiener klin. Woch., 1901. XXXI. ARSENIC. Some of the less active preparations of arsenic, such as the sul- phides, Realgar (As 2 S 2 ) and Orpiment (As 2 S 3 ), have been known in therapeutics since the beginning of the Christian era, but this metal was brought into especial prominence in later times through the fre- quent use of the more dangerous oxides in criminal poisoning. Thus the notorious Aqua Tofana of the sixteenth and seventeenth centuries owed its activity to the presence of arsenic, and various arsenical com- pounds have been used up to the last few years more largely than al- most any other poison in suicide and homicide. This is to be ex- plained by their having been widely employed in the arts, and thus being readily accessible to all, and by the general recognition of their poisonous nature. Of late years intentional arsenic poisoning has be- come somewhat less common, though on the other hand, accidental poisoning is still met with not infrequently, especially in the chronic 604 INORGANIC SALTS, ACIDS AND BASES. forms. Many of these chronic cases are extremely difficult to diagnose, and probably often pass unrecognized by the attending physician. In view of this fact it seems desirable that more stringent measures should be taken to reduce the use of arsenic in the arts, and especially to pre- vent its being brought in contact with food. The danger of the use of the green arsenical dyes, such as Scheele's Green (arsenite of cop- per), and Schweinfurt's Green, or Paris Green (arsenite and acetate of copper), is now generally recognized, but arsenic is still used in the preparation of other colors, and these may give rise to poisoning from the imperfect removal of the metal. It has also been used in dilute solution to preserve food, and a solution is often sprayed upon grape vines and other plants to preserve them from the attacks of insects. Poisoning has occurred from these sources and is difficult to diagnose, as it is in some cases impossible to find the means by which the arsenic enters the system. A widespread epidemic of poisoning in England in 1900 drew attention to a source of arsenic which had not up to that time received the attention it merited. Several thousands of persons suffered from arsenic being contained in cheap beers made from glu- cose, in the manufacture of which sulphuric acid had been employed. The sulphuric acid was formed from iron pyrites containing arsenic, and the poison was carried from the sulphuric acid with the glucose into the beer. Sulphuric acid is used in the manufacture of so many drugs, foods and other substances in constant use, that this intimation that it may convey arsenic into articles where its existence has not hitherto been suspected, is of the gravest importance. Metallic arsenic is insoluble in water, and passes through the alimen- tary canal for the most part unchanged and without action, but it is possible that small quantities may be oxidized to arsenious acid in the stomach and intestine under some conditions. Some symptoms have been observed when it is rubbed on the skin in a state of fine division, and these are probably due to its absorption in the form of an oxide. The characteristic " arsenic " action is induced by the salts of arsenious acid (AsO 3 H 3 ), and by its anhydride (As 2 O 3 ) which is often known as arsenic, and which exists in the tissues as arsenites. Arsenic action is therefor due, not to the element, but to the ion of arsenious acid. The anhydride ^nd salts of arsenic acid (H 3 AsO 4 ) cause similar symp- toms, but are lest poisonous and act more slowly than those of arse- nious acid, and may probably owe their effects to the formation of arsenites in the tissues. The action being due to the ion and not to the element, it necessarily fol- lows that compounds from which the ion is not liberated, do not induce the arsenic action, or do so only when they are changed to bodies which can dissociate the arsenious acid ion. Thus organic arsenic combinations in which the metallic atom is directly attached to carbon are only feebly poison- ous, but in course of time seem to be changed to arsenious acid in the tissues, and then cause typical poisoning. The best known of these are cacodylic oxide ((CH 3 ) 2 As 2 O(CH 3 ) 2 ) and cacodylic acid ((CH 3 ) 2 AsOOH). Arsenical compounds of the aromatic series have also been examined pharmacologically and induce arsenic symptoms when given in large quantities. This poison- ous action is again due not to the undecomposed molecule, but to the arseni- ous acid derived from it, some of which is found excreted in the urine. ARSENIC. 605 Arsenious acid, which in the following pages will be taken as the representative of " arsenic " action, has a somewhat sweetish taste, and is therefore not so likely to be detected by the victim as many of the other poisons. Symptoms. In large quantities arsenic very often causes no symp- toms for half an hour or more, but then the patient complains of a feeling of constriction in the throat, of difficulty in swallowing, and of discomfort in the stomach region. This soon increases to violent pain, and is accompanied by vomiting, and later by watery diarrhoea. The stools are at first of ordinary diarrhceic appearance, but later re- semble the " rice-water " stools of cholera, in that they consist almost entirely of minute shreds of disintegrated mucous membrane suspended in a serous fluid ; sometimes, however, they are clear and gelatinous in appearance. In some cases, blood appears in the vomited matter and also in the stools, but this is not by any means an invariable fea- ture. The urine is diminished, or entirely suppressed, from the great amount of fluid eliminated by the stomach and bowel. These symp- toms from the alimentary tract are accompanied by giddiness, cramps in the muscles, headache, and soon by collapse, with cold, damp skin, pallor, feeble pulse and weak, sighing respiration ; this later passes into coma, and death follows with or without convulsions. In cases in which the dose is smaller than the fatal one, or in which much of the poison is eliminated by vomiting, the patient may recover without further symptoms than those already described. Frequently, how- ever, he recovers from the acute symptoms only to develop those of chronic arsenical poisoning. In some instances it is said that no symptoms are present except those of collapse and coma. In acute poisoning death may occur within 24 hours, but more frequently the patient lives for 24 days or longer, and then succumbs to exhaustion. The fatal dose is very uncertain, because arsenic is very insoluble, and much of the poison may be thrown up by vomiting, or pass out in the stools unabsorbed. Thus in some cases, recovery has followed after very large quantities, while in others about 0.1 G. (1 J grs.) has proved fatal. Chronic Arsenic Poisoning may arise from a single large dose, the effects persisting for weeks or months after the ingestion and new symp- toms arising as the earlier ones disappear ; more frequently, however, it is induced by the prolonged absorption of small quantities. The milder symptoms may arise from its therapeutic use, but typical cases are generally due to the presence of arsenic in the form of dyes in wall paper or clothes, or in stuffed animals in the rooms inhabited by the victims, or to the constant handling of arsenical pigments and other compounds in mines and manufactories. Widespread poisoning has been observed from the use of wines containing arsenic at Hyeres in France, from milk diluted with arsenical water in London, and from beer in the Manchester district. In these last cases the arsenic was in solution, but it often seems to be inhaled in the form of fine dust, which falls from the walls or other objects. It has been suggested that the 606 INORGANIC SALTS, ACIDS AND BASES. arsenic dyes are decomposed by microbes and the volatile arseniuretted hydrogen (AsH 3 ) inhaled, but there seems no reason to suppose that this is the case, and the inhalation of fine particles is a sufficient ex- planation. The symptoms of chronic arsenic poisoning, which are often very obscure, may be divided into three phases. ^ In the Jurst of these, the patient complains of weakness and languor, loss of 1 appetite, some nausea and occasionally vomiting, with a sense of heaviness and discomfort in the stomach. Diarrhoea may be present, but is often absent, and in fact some constipation may occur. In the second phase the conjunctiva is often red and inflamed, and ^oT^coryza appear, with sneezing,Tioarseness and coughing, from a catarrhal condition of the mucous membranes of the nose and larynx. Some swelling of the liver and jaundice may occur, but these are not generally well marked. Skin eruptions of various forms pap- ular, vesicular, or erythematous are generally noted ; very often the epidermis falls off in fine brownish scales, or in tho hands and feet in large flakes (keratosis) ; a curious pigmentation is very common, the skin assuming a dark metallic color resembling in extreme forms that produced by rubbing a lead pencil upon it (arsenic melanosis). This pigmentation is much more marked in persons of dark complexion than in fair people in whom it may be indistinguishable from ordinary freck- les ; it generally disappears when the patient is removed from the poi- sonous atmosphere, but has been permanent in some cases. In pro- longed poisoning the eruptions may simulate almost any form of skin disease, and the hair and nails fall off. Herpes is not infrequently observed and points to nervous disturbances such as are prominent features in the next phase. These phases are not always distinct in cases of poisoning, and very often some of the symptoms of the second phase may appear before any marked disorder of the digestive tract. In the prolonged thera- | peutic use of arsenic, the first indications of commencing poisoning are redness, suffusion and swelling of the conjunctiva and eyelids, and dryness of the nose and throat, as in coryza. On the other hand, in workmen exposed to arsenical dust, the first symptoms may arise from the skin or from bronchial irritation. ? The third phase is marked by disturbance of sensation and motion in localized areas, generally in the hands and feet (peripheral neuritis). It is often ushered in by intense persistent headache or by acute pain located around the knee, ankle or foot, less frequently in the wrist and hand. The patient complains of formication in the ex- tremities, and of the discomfort caused by the pressure of the bed- clothes on the feet and legs. The palms of the hands and the soles of the feet are often red, swollen and extremely sensitive to touch (ery- thromelalgia), and pressure on the muscles induces the most intense pain. Later, sensory paralysis may set in, especially in the extrem- ities, and the less acute sense of touch in the feet and hands induces symptoms resembling those of locomotor ataxia. The sensitiveness to AKSENIC. 607 heat and cold may be exaggerated or dulled, or sometimes heat is not appreciated, while cold causes intense pain. The sense of pain varies in different cases, in some being abnormally acute, in others deadened. These sensory disturbances are followed in severe poisoning by motor paralysis which generally appears in the extensor muscles of the toes, later in the peronei muscles. More rarely the flexor muscles of the leg and foot are involved, and in some cases the affection commences in the extensors of the hand and fingers. As a general rule the paralysis is confined to the extremities, but in some cases it has been found to in- vade the trunk. It is generally, but not invariably, symmetrical, and the muscles affected atrophy rapidly, and contract weakly to the gal- vanic shock, not at all to the faradic except in the beginning of the affection. This lessened excitability of the muscles sometimes appears before the typical degeneration reaction is observed, but is then fol- lowed by it later. The muscles are abnormally excitable to mechanical stimulation, however, while the tendon reflexes are generally entirely absent. There is sometimes some difficulty experienced in diagnosing arsenic from lead paralysis, but in the former there is often a history of acute poisoning, while the latter is almost invariably due to pro- longed absorption. JDisturbances of sensation are much more com- mpjiJELarsenic than in lead palsy, and jn the latter the forearm mus- cles are generally affected first, in the former those of the leg. In arsenic poisoning atrophy is said to occiif much more rapidly, and there is no line on the gums. Another condition which presents still greater difficulties in diagnosis is alcoholic neuritis. But in the latter skin eruptions are extremely rare, coryza is not present, and there are generally more marked brain symptoms than in arsenical cases. In doubtful cases the urine and the hair of the patient should be tested for arsenic. Arsenic paralysis may appear as early as three days after an acute intoxication, but is commonly observed later and may occur only after 3-4 weeks. Some authors have asserted that in chronic arsenic poi- soning there is a paralysis of the sexual powers (anaphrodisia), and ascribe this to an action on the nerves of the sexual organs, similar to that observed in the extremities, but this symptom is not by any means generally present, and, in fact, abnormal sexual excitement has been noted in some cases. In very prolonged arsenic poisoning the patient may sink into an apathetic, semi-idiotic condition, or may become epileptic. In most cases the symptoms slowly disappear when the poison is removed, but even slight paralysis may last for many years before it is entirely cured, and after complete degeneration of the muscles little improve- ment is to be expected. The contractures which follow are generally due to the unopposed action of the sound muscles, but sometimes arise from the shortening of the paralyzed ones. Arsenic poisoning generally occurs from the inhalation of particles of the drug, or from swallowing solutions or powders. But the same symptoms have been elicited in animals by subcutaneous or intravenous 608 INORGANIC SALTS, ACIDS AND BASES. injection, and some cases of poisoning in man are recorded in which the arsenic gained entrance to the body through its application to burns or other surfaces denuded of skin, or from its application to mucous membranes, as in the vagina. Action. The symptoms of arsenic poisoning, as far as the Alimen- tary Canal is concerned, resemble those of corrosive poisoning so closely that it was long supposed that arsenic had some destructive effect upon albumins, resembling that of the acids and corrosive metals. Many attempts to form a combination between proteids and arsenic have been made, but have proved fruitless ; arsenites and arsenious acid do not coagulate proteids or change them in any way, except when applied in such enormous quantities as never reach the stomach. The action of arsenic on the alimentary canal cannot be explained as due to any ordinary form of corrosion, therefore, although the symp- toms and the post-mortem appearances resemble in many points those of the corrosive poisons. Thus the mucous membrane of the stomach is generally found red and swollen, either in patches or throughout its whole extent. Hemorrhages into it are occasionally present, but are not by any means a constant feature, and little or no erosion can be made out as a general rule. The epithelial coat can be rubbed off very easily, and is found to be in a state of fatty degeneration. It sometimes resembles a false membrane and has been described as such, but closer examination shows it to consist almost entirely of the degen- erated epithelium. This destruction of the epithelium is often con- fined to particular parts of the organ, affecting the posterior wall chiefly in man. Where arsenic has been swallowed in powder, and has remained in contact with the wall for some time, the congestion is often more marked, and here even erosion may appear. In some cases no congestion of the stomach is met, the only lesion consisting in cloudy swelling and fatty degeneration of the gland-cells, similar to that mentioned under phosphorus. The intestine presents very similar appearances, the mucous mem- brane being swollen and congested, more especially around Peyer's patches. It contains a quantity of thin fluid with flakes of membrane, resembling exactly the rice-water stools of cholera, and in fact it may be difficult to distinguish the intestine of arsenic poisoning from that of cholera. Small particles of arsenic are often found in the stomach and bowel, even after profuse vomiting and purging. In some cases the redness a^d congestion extends up to the throat and causes a feeling of soreness in the mouth. The first explanation suggested for the action of arsenic on the ali- mentary tract, namely, the corrosive action of the drug, has been shown to be incorrect, for the same symptoms arise when arsenic is absorbed from the subcutaneous tissue, or from the broken skin. This does not entirely preclude the corrosive action, for arsenic, though ab- sorbed from the skin, may be excreted by the mucous membranes, and thus corrode them ; and, as a matter of fact, small quantities (up to a milligram) have been isolated from the stomach and intestines, when ARSENIC. 609 arsenic was injected intravenously in animals, but these are obviously insufficient to cause such violent symptoms. Besides, as has been stated, arsenic does not change proteids in solution as the corrosive poisons do, and cannot therefore elicit typical corrosion. Boehm and his pupils have suggested that the gastro-intestinal action of arsenic is due, not to any direct action on the epithelium, but to the vascular changes induced by it. They suppose that the extreme dila- tation of the intestinal vessels and capillaries gives rise to the conges- tion and swelling, and this in turn to the destruction of the lining membrane, perhaps by the exudation of fluid beneath the epithelium. This transudation of fluid is certainly in accord with the watery char- acter of the stools in arsenic poisoning, but the explanation does not Beem entirely satisfactory, for it fails to account for the fatty degener- ation and the cloudy swelling of the epithelium, which are in some cases the only lesions found here. The fatty degeneration is not con- fined to the stomach and bowel, but involves a number of other organs, although it is not as a general rule so widely distributed as in phos- phorus poisoning. Arsenic then must be considered to have a specific action in causing fatty degeneration of the epithelium of the stomach and intestine. This in itself is sufficient to explain many of the symptoms from these organs, although it may well be that the vascular action is the cause of the excess of fluid in the intestine, and in fact, the fatty degeneration alone is insufficient to explain this feature, which is absent in phosphorus poisoning. In cases of poisoning where the arsenic is taken by the mouth, and especially when large quantities of dry arsenious acid are swallowed, the specific action on the epithelium and the vascular action are probably intensified by the direct contact of the poison. Filehne is disposed to regard the corrosion of the stomach which is sometimes observed, as due to the digestion of the epithelium killed by arsenic, and not to the direct action of the poison. In therapeutic doses arsenic is said to increase the appetite and pro* mote digestion, an effect which may perhaps be due to the specific ac-> |tion on the epithelium, this in its milder forms proving of advantage* *to the organ, though in excess it leads to its degeneration. The action of arsenic on the Circulation has been investigated by several authors, who have obtained discordant results. In the frog the heart is slow and weak, eventually becomes irregular, and ceases in diastole after comparatively small doses ; the action seems to be a direct paralysis of the muscle. In the mammal the heart is less affected ; it is somewhat accelerated by very small doses injected in- travenously, but is slowed by larger ones, and the inhibitory mechan- ism does not seem to be altered. The blood-pressure is often increased at first, but soon falls after large doses. The cause of this fall has been a matter of dispute, but the most recent investigator (Pistorius) attempts .to bring the results of his predecessors into accord by ex- plaining that the vaso-motor centre and later the splanchnic nerves lose their control over the vessels. When the pressure begins to fall, it 39 610 INORGANIC SALTS, ACIDS AND BASES. may be restored by stimulation of the vaso-motor centre, but this loses its effect later, although direct stimulation of the splanchnic nerves still increases the tension. Still later the splanchnics lose their action through paralysis of their ends, or of the vascular walls, while the other vaso-constrictor nerves are still capable of narrowing the vessels ; for instance stimulation of the cervical sympathetic still causes pallor of the ear, so that this action of the drug seems to be confined to the splanchnic area. The dilation of the mesenteric vessels leads to very marked congestion of the stomach and bowel, and along with the les- sened efficiency of the heart reduces the blood-pressure to zero. Some evidence has been brought forward that under arsenic the capillaries permit the passage of fluid into the tissues more readily than normally ; this may explain the appearance of oedema in cases of poisoning and also the large amount of fluid in the stools and vomited matter. The Respiration is somewhat accelerated at first by the intravenous injection of small quantities of arsenic, but afterwards returns to its normal rhythm. In cases of poisoning in man the respiration does not seem to be much affected until late, but it ceases before the heart, probably from the exhaustion and low blood-pressure, and not from any specific action on the centre. The action of arsenic on the Central Nervous System has been re- peatedly examined. A descending paralysis is elicited in the frog, the animal first losing its spontaneous movements, and then its reflexes, and the terminations of the motor nerves being involved only very late in the intoxication. There is no question that the brain, spinal cord and nerve ends are directly acted on in these animals, for paralysis is elicited by arsenic much sooner than by arrest of the circulation by excision of the heart. In mammals there are generally no certain in- dications of direct action on the nervous system in acute poisoning, for the weakness and prostration, and the final loss of consciousness and coma may be attributed to the exhaustion from the gastro-intes- tinal effects rather than to the centres being immediately affected. At the same time the acceleration of the respiration in the beginning of the intoxication, and the paralysis of the vaso-rnotor centres, would seem to point to a direct action on the medulla oblongata. The pathology of the nervous disturbances observed in chronic poi- soning, and often after a single large but not immediately fatal dose, is still obscure, and probably bears no relation to the symptoms observed in animals in acute poisoning. In many cases of paralysis, there is distinct tenderness along the course of the nerve trunks, which would suggest peripheral neuritis as the cause. Kreyssig could find no altera- tions in the spinal cord in cases of poisoning in animals except occa- sional haemorrhages, which did not seem to be of consequence. Jaschke and Alexander observed peripheral neuritis in animals, and the ques- tion therefore seemed decided in favor of the peripheral origin of the symptoms. More recently, however, in two autopsies of persons suffer- ing from arsenical paralysis, undoubted lesions of the spinal cord have been described. The symptoms point so unmistakably to peripheral ARSENIC. 611 neuritis as the cause, however, that the almost universal opinion is that the nerve fibres are the primary point of attack, although in severe cases the affection may involve the nerve cells in the cord in addition. The peripheral nerves and the muscles are little affected by arsenic in acute poisoning ; but the muscles of a frog poisoned with arsenic are found to lose their irritability somewhat sooner than those of one whose circulation and central nervous system have been destroyed, so that the poison has some deleterious effect on them also. The unbroken Skin is not affected by arsenic, unless when it is ap- plied repeatedly or allowed to remain in contact with it for some time, when it may give rise to redness, pustules or vesicles and later to violent erysipelatoid inflammation. It has not, however, any such corrosive action on the skin as is possessed by strong acids, and the subcutaneous injection of arsenic is not painful. It is more active when applied to denuded surfaces and to the mucous mem- branes, destroying them to some depth and causing acute pain, but even here it acts more slowly than ordinary caustics. It seems to act only upon living cells, and unlike acids and alkalies, forms no combi- nations with the dead tissues. The local effects of arsenic on the skin are seen only in workmen handling arsenic, as in color factories, in which affections of the skin of the face, hands and scrotum are by no means rare. In arsenic poisoning skin eruptions are common, and may be due in part to circulatory disorders, but are to be ascribed for the most part to the direct action of the drug on the skin. This appears to acceler- ate the growth and proliferation of the epithelium, which is found to be increased in thickness, but which in very severe cases shows signs of atrophy and degeneration. Arsenic has been found in ap- preciable amount in the hair, epidermal scales, and in the fluid of a blister in patients treated with it, and changes in the condition of the skin in animals have also been observed. Thus Ringer found the epidermis of the frog peel off with great ease when it was poisoned with arsenic, and Nunn ascribes this to the softening of the protoplasm of the deeper cells of the epidermis ; analogous changes have been ob- served in the cornea. The melanosis of arsenic poisoning seems to be due to the deposi- tion not of an arsenical compound, but of some organic product in the deeper layers of the corium. The symptoms of irritation of the mu- cous membranes of the eye, nose and larynx are analogous to the skin eruptions. The action of arsenic on The Blood is still obscure, although it is fre- quently prescribed in various forms of anemia. In chlorosis and in normal persons, it is said to diminish the number of the red corpuscles, but not to alter the total hemoglobin of "the blood. In a case of pernicious anaemia recently examined by Engel, it was found that ar- 612 INORGANIC SALTS, ACIDS AND BASES. senic increased the number of young newly formed red cells while the number of more mature corpuscles was diminished. Bettmann states that in subacute poisoning in rabbits, the red cells and hsemoglobin are diminished, and nucleated red cells appear in the blood in some num- ber ; he holds that arsenic acts on the blood, and also on the blood- forming organs. Stockman and Greig found the blood cells and haemoglobin unaltered by arsenic in normal animals, but describe the bone-marrow as evidently in a state of unusual activity, indicated by its increased vascularity, greater number of red blood corpuscles and lessened fat cells. In some cases of arsenic poisoning Fever is observed ; this does not seem due to any specific action of the drug but to the inflammation of the mucous membranes and the skin. The Metabolism is affected by a poisonous dose of arsenic in the same way as by phosphorus, but the alteration is not generally so marked and is liable to be overlooked, owing to the more intense action on the alimentary canal. The nitrogen of the urine is considerably greater than that of inanition, but it is not quite clear whether this is due to an increase in the urea or to other nitrogenous substances. The ammonia is probably augmented, for a considerable amount of lactic acid has been obtained from the urine, and the alkalinity of the blood is reduced owing to the formation of this acid in excess. The glycogen of the liver disappears entirely, and the liver seems incapable of forming it from the sugar of the food. Lesion of the medulla oblongata (diabetes puncture) does not cause glycosuria after arsenic, but curara and other drugs are still capable of eliciting this symptom. The fatty degeneration of the epithelium of the stomach and intestine has been mentioned already, but this alteration is not confined to these tissues, being found in the liver and kidney, in the muscle cells of the heart, blood vessels and striated muscles, and in the lining epithelium of the alveoli of the lungs. Small necrotic foci have been observed by Wolkow in the liver, along with signs of active division of the parenchymatous cells, as in phosphorus poisoning. Many of these changes admit of the same explanation as that given in phosphorus poisoning, namely, that arsenic lessens the oxidation of the tissues and causes fatty degeneration of the cells of various organs ; it may also increase the waste of the proteids of the body directly, but the increase in the nitrogen of the urine may perhaps be sec- ondary to the other features. Attempts have been made to demonstrate the lessened oxidation by estimating the respiratory gases, but here, as in phosphorus, no satisfactory results can be obtained by this method, owing to the slow progress of the intoxication, and to the diminished movement and retarded digestion ; these in themselves are sufficient to cause a marked fall in the output of carbonic acid and in the absorp- tion of oxygen, without any direct action on the tissue cells. The metabolism is less affected by arsenic than by phosphorus, however, for the fatty degeneration is less marked and less lactic acid is ex- creted. Nencki and Sieber have also shown that benzol can be oxi- ARSENIC. 613 dized to phenol in animals poisoned with arsenic, while in phosphorus poisoning the tissues are unable to effect this. The fatty degeneration may have the same results as in phosphorus poisoning. The liver is somewhat enlarged and the pressure on the bile ducts prevents the escape of bile into the intestine, and thus induces jaundice and the appearance of bile pigments and bile acid in the urine. Jaundice is seldom, however, a very marked feature in arsenic poisoning, and is often entirely absent. The bile is said to con- tain albumin, red blood cells, and casts as in phosphorus poisoning, but does not present other changes except immediately before death (Pilzecker). The prolonged administration of arsenic in quantities insufficient to produce chronic poisoning is reputed to have some effect on the Growth and Nutrition. It is difficult to obtain accurate data in regard to this point, and while the improvement in nutrition is attested by a number of independent observers, other equally careful investigators have not been able to confirm their results. Gies treated some of a litter of young rabbits with arsenic in minute doses for several weeks, and found that they weighed more, and were larger in every way than the untreated animals ; the subcutaneous fat was much greater in amount, the bones were longer, and the muscles more developed. The long bones presented the appearance described by Wegner under phos- phorus treatment, being longer and containing more dense bone both in the shaft and the epiphyses. Female rabbits treated with arsenic bore young of abnormal size and weight ; Gies, in fact, supposes that their size caused difficulties in their passage through the pelvis, for they were all born dead. Several other observers have described a more rapid growth and greater activity in young animals treated with arsenic, and an increase in weight is often noted in man. On the other hand Stockman and Greig observed no change in the growth of animals under prolonged treatment with arsenic, and found that the only tissues affected were the growing bones, which appeared denser than usual. The improvement in nutrition has not been explained, though a slight decrease in the nitrogenous excretion and in the amount of nitrogen in the stools has been noted by Weiske, who holds that more of the food is utilized by the digestive apparatus, and at the same time, less proteid is decomposed in the tissues. The change in the amount of nitrogen excreted is so small, however, that doubt may be entertained whether it may not be due to unavoidable errors in the estimation, and other investigators have been unable to detect any alteration attribut- able to the drug. Fresh investigation of this point is thus required before certainty can be reached regarding the effects on the nutrition, and still more regarding the explanation of the alterations. When small quantities of arsenic are taken habitually, Tolerance is established, and the dose may be gradually increased until it far ex- ceeds that which would be poisonous in ordinary persons. This is the explanation of arsenic-eating which is known to exist in different parts of the world, but which is most widespread and best known in 614 INORGANIC SALTS, ACIDS AND BASES. Styria and the Tyrol. The peasants there indulge in the poison habit- ualty, and believe that it enables them to work better, and in particular to climb the mountains with less effort and less respiratory distress. They also credit it with improving their complexions and general ap- pearance, and give it to their horses in order to render their coats more smooth and glossy, and to make them stronger and fatter. Doubt was formerly entertained as to the truth of the statements made regarding the doses used by these people, but this was definitely settled by Knapp, who administered 0.4 G. (7 grs.) of arsenious acid to one of the peas- ants at Graz without inducing any effects whatsoever. Large quanti- ties of arsenic have also been isolated from the urine of arsenic eaters, showing that much of the drug is absorbed. Arsenic-eating is said to be indulged in to a considerable extent by young women in some coun- tries with the object of improving the complexion and figure, and cases of arsenic habit have been described in different parts of America and elsewhere. As far as can be observed the habit is not deleterious, for the Styrian peasants live to old age, and no symptoms attributable to the poison have been noted. As a general rule large doses are taken once or twice a week, and no fluid is swallowed for some time after- wards, so that some of the poison may pass through the bowel unab- sorbed. No tolerance for arsenic has been established in animals, even by prolonged treatment with minute doses. As a contrast to the Styrian peasants, the miners of Reichenstein may be mentioned, who are constantly exposed to arsenic owing to its being contained in large quantities in the ore. These people are de- scribed by Geyer as shortlived, very subject in childhood to severe rickets and in adult life to dropsies and respiratory diseases ; they offer little resistance to microbial infection and frequently present the skin and nervous symptoms of arsenic poisoning. Why arsenic should be beneficial or at any rate harmless at Graz, and so deleterious in Reichenstein, it is impossible to state at present. But it is not unlikely that the contrast may rest upon differences in the general nutrition, for Delepine and others have found that animals supplied with abundant food and in good hygienic conditions survive under chronic arsenic poisoning much longer than less well nourished ones. This difference in the nutrition may also explain the fact that in epidemic poisoning, as in the Manchester cases, comparatively few of the persons exposed to the poison exhibited any symptoms from it. Arsenic is Excreted for the most part in the urine, to a much smaller extent in the stomach and bowel and along the respiratory mucous membranes. Traces are eliminated in the skin secretions, in the hair, and in the milk, and fatal intoxication has been observed in a child from the milk of its mother, who was suffering from acute poisoning. In the urine arsenic appears in part in organic combinations, in part, according to Selmi, in the form of a volatile organic base, which is in- tensely poisonous and causes convulsions in frogs. Arsenic is only slowly excreted ; it is stated to have been detected in the urine 2-3 months after its administration, but it has been shown to occur in the ARSENIC. 615 urine of a number of persons who presented no signs of poisoning and had not been treated with arsenic, so that it is possible that in those cases of slow elimination the arsenic of the urine did not arise from the single administration, but from its subsequent absorption from some other source, such as the water or air. There is no question, however, that it remains in the system longer than many other poisons. It is probable that the effects, especially the paralysis, last long after the drug has been excreted, lesions having been induced which are only slowly recovered from. Arsenic is found in largest quantity in the liver, in which it forms a firm combination with the nucleins ; it is also deposited in the kid- ney, in the walls of the stomach and intestine, and in the spleen and lungs. Much smaller quantities are found in the muscles and in the nervous tissues, which were formerly supposed to contain more than the liver. It is stated that in cases of poisoning arsenic is found in the white matter of the brain in much larger proportion than in the cortex. In the blood most of the arsenic is said to be contained in the blood cells, comparatively little being free in the plasma. Arsenic has been detected in the cancellous bones of the skull and vetebrse, after it had disappeared from all the other organs. Arsenic is poisonous to many of the lower forms of life, as well as to the vertebrates ; thus it has been found that its presence in comparatively dilute solution (one part of arsenious acid in 30,000 parts of water) hinders the development of, and eventually kills alga3 and the seeds of the higher plants. On the other hand, moulds grow abundantly in a solution of arsenite of potash (1 per cent.) containing some organic matter, and the alcoholic fer- mentation proceeds in the presence of arsenic, although it is somewhat re- tarded at first ; very dilute solutions of arsenic even accelerate the fermen- tation, as is true of most other antiseptics. Arsenious acid is only about one-tenth as strong an antiseptic as perchloride of mercury, and the spores of anthrax are destroyed only after ten days in a one per mille solution. It has therefore a greater antiseptic power, than many of the other acids, but compared with its action on the higher forms of life, it is but slightly poisonous to the fungi. It seems to have no effect on the activity of the ferments, such as pepsin, myrosin and emulsin. The arsenates are much less harmful to lowly organized forms, for seeds and algae as well as moulds grow in a neutral solution abundantly, and even the infusoria do not seem injured by it to any marked degree. Apparently these plants and animals are incapable of reducing it to arsenious acid, and are therefore not more affected by it than by other acids. The bodies of persons poisoned with arsenic are said to remain undecom- posed for a remarkably long time, and to tend to become mummified. The statement is still disputed, but is vouched for by a number of authorities. It is certainly not invariably the case, and little weight is to be laid upon mummification in determining whether arsenic poisoning was the cause of death in exhumed persons. No account of the pharmacology of arsenic would be complete without mention of the theory advanced by Binz and Schulz to explain its action. They suppose that arsenious acid is oxidized to arsenic acid by the living tis- sues, and the arsenic acid again reduced to arsenious. In this way oxygen is alternately withdrawn from, and supplied to the protoplasm, and this alter- nate reduction and oxidation they suppose to be the essential feature of the action of arsenic. The grounds on which this explanation is based must be sought in the numerous papers on the subject by these authors, and it may 616 INORGANIC SALTS, ACIDS AND BASES. suffice here to state that while arsenic acid appears to be reduced, and arsenious acid oxidized in the tissues, these processes are probably only gradual. Otherwise it would be difficult to explain how arsenious acid is so much more poisonous than arsenic acid, for if the latter were readily re- duced to arsenious acid it would be equally toxic. Arsenic and phosphorus are included in one group in chemistry, and their effects on living organisms present sufficient resemblance to jus- tify their association in the pharmacological system. The mucous membranes and the skin are more affected by arsenic, however, and the circulation is more rapidly depressed, while the fatty degeneration of the protoplasm of the vertebrates is much more prominent in phos- phorus poisoning. ,The differences between their effects are more in degree than in kind, and there seems no question that their ultimate action on protoplasm is of the same nature. It is to be noted, how- ever, that there is no reason to suppose that phosphorus owes its action to any of its numerous compounds with oxygen, while it is probable that the oxides of arsenic alone are capable of modifying vital functions. The Sulphur Compounds of arsenic are entirely insoluble and are therefore not absorbed as such, but it seems likely that small quantities of arsenious acid are formed from them in the intestine by microbes. Commercial orpi- ment often contains large amounts of arsenious acid. Arseniuretted Hydrogen (AsH 3 ) is an exceedingly poisonous gas, which has caused a number of fatal accidents from being inhaled accidentally in chemical laboratories. One source of danger is the liberation of hydrogen from acids by the action of zinc, which often contains arsenic and therefore gives rise to this gas. It differs entirely from the oxides of arsenic in its ac- tion, and there is no reason to suppose that it forms these in the body. Pos- sibly traces of arseniuretted hydrogen are formed from arsenious acid in the intestine, but in insufficient quantities to have any appreciable effect. Ar- seniuretted hydrogen acts as a molecule, AsH 3 , arsenites as ions, and the fact that both molecule and ion contain an atom of arsenic, does not neces- sarily entail that their effects shall bear any resemblance. Arseniuretted hydrogen acts by destroying the red corpuscles of the blood, and induces intense headache, nausea and vomiting, prostration and faint- ing fits, cyanosis and collapse. Haemoglobin, methsemoglobin, hasmatinand occasionally blood are passed in the urine, and more rarely the stools contain blood. Sometimes the urine is entirely suppressed from the tubules being plugged with blood cells and debris, and intense icterus appears from the formation of excess of bile pigment from the haemoglobin of the disinte- grated corpuscles. (Edema of the lungs or sudden failure of the heart is the cause of death. Some of the gas is excreted by the lungs, and may be rec- ognized by its garlic odor, and some arsenic appears in the urine, but it is not known in what form. PREPARATIONS. ARSENI TRIOXIDUM (TL S. P.), ACIDUM ARSENIOSUM (B. P.) (As 2 O 3 ), arsenous or arsenious acid anhydride, white arsenic, ratsbane, forms a white powder, or opaque, porcelain-like masses, or a transparent, amorphous sur- face like glass. It dissolves slowly in cold water, the glassy variety requir- ing about thirty, the porcelain about eighty parts of water. It is almost tasteless and has no odor. 1-5 mgs. (sV-i 1 * gr.), in pill or solution, after meals. The "Asiatic" pill consists of arsenic, black pepper and liquorice. Liquor Acidi Arsenosi (U. S. P.), Liquor Arsenici Hydrochloricus (B. P.), a one per cent, solution of arsenous acid acidulated with hydrochloric acid. 0.05-0.5 c.c. (1-8 mins.), 3-5 drops three times daily, after meals. ARSENIC. 617 LIQUOR POTASSII ARSENITIS (U. S. P.), LIQUOR ARSENICALIS (B. P.), Fow- ler's solution, contains one per cent, of arsenous acid neutralized with bicar- bonate of potash, to which compound tincture of lavender is added to give color and flavor. 0.05-0.5 c.c. (1-8 mins.), 3-5 drops three times daily, after meals. Sodii Arsenas (U. S. P.) (Na 2 HAsO 4 + 7H 2 O) forms colorless, odorless crys- tals, very soluble in water, with a mild, alkaline taste. 1-5 mgs. (sV-rV gr.). Sodii Arsenas (B. P.), Sodii Arsenas Exsiccatus (U. S. P.) (Na 2 HAsO 4 ), is prepared from the ordinary arsenate (U. S. P.) by driving off the water of crys- tallization, and forms a white powder. ^VrV r - Liquor Sodii Arsenatis (U. S. P., B. P.), Pearson's solution, a one per cent, solution of the sodium arsenate of the respective pharmacopoeias. 0.05-0.5 c.c. (1-8 mins.). Arseni lodidum (U. S. P.), Arsenii lodidum (B. P.) (AsI 3 ), glossy, orange- red crystals with an iodine odor and slowly giving off iodine in the air ; it is soluble in 7 parts of water, but the solution soon decomposes into arsenous and hydriodic acids. 3-10 mgs. (^o-i gr.). LIQUOR ARSENI (ARSENII, B. P.) ET HYDRARGYRI IODIDI (U. S. P., B. P.), Donovan's solution, contains one per cent, of arsenic iodide and one per cent, of red mercuric iodide. This solution is clear and yellowish, without odor, but with a harsh metallic taste. 0.3-1.3 c.c. (5-20 mins.), after meals. Ferri Arsenas. (See Iron.) Some mineral waters contain arsenic, that of Levico as much as 8 mgs. per litre. Therapeutic Uses. The action of arsenic as ascertained from ex- periments on the lower animals and from cases of poisoning in man throws little light on its use in therapeutics, and so little is known of the pathology of most of the conditions in which it is found of benefit, that no attempt can be made to bring the two series of observations into relation. Arsenious acid has been used externally as a caustic, formerly in various forms of malignant disease, more recently in lupus, in which it is said to destroy the diseased surface while leaving the healthy skin unaffected. It has been superseded, however, by the introduction of surgical measures, such as scraping with the sharp spoon. Arsenic in substance is still used in dentistry to destroy the pulp in decayed teeth. Internally arsenic is used in malarial disease, especially in invete- rate cases in which there in much cachexia. In acute cases it is also of benefit, but is much less certain in its effects than quinine, and it is very questionable whether it acts on the malarial organism, for its effi- cacy often seems due rather to its improving the general nutrition and lessening the cachexia and wasting. Many authorities, in fact, depre- cate the use of arsenic in acute malaria, and would limit its use to the cachexia of old disease, while others advise its use with iron in ordinary cases, after the acute stage has been successfully treated with quinine. Arsenic has also been used with benefit in neuralgia, especially when it assumes a periodic character, and in chronic rheumatism, but in many cases no definite improvement follows, and the conditions under which it is of value cannot be more accurately defined at the present time. Old cases of chorea often improve under arsenic, which may imply some action on the central nervous system, although, as has been stated, little alteration in the nervous functions is observed in ani- 618 INORGANIC SALTS, ACIDS AND BASES. mals except under very large doses. Asthma has also been treated with arsenic given by the stomach, or by the inhalation of arsenic from smoking cigarettes made with arsenical paper. Small doses of arsenic are often of service in increasing the appetite and improving the general condition in diseases accompanied by cachexia, want of appetite, general weakness and apathy. In pernicious anaemia, arsenic is said to be beneficial, but the im- provement is only temporary. Many forms of skin disease are treated with arsenic, some of them with the happiest results. Thus in psoria- sis, chronic eczema and lichen ruber, marked improvement or complete recovery often dates from the beginning of the arsenic treatment. It is generally advised only in the chronic forms, and is said to be posi- tively deleterious during the earlier stages of rapid cell proliferation. In lymphoma, arsenic has been given internally and also by direct injection into the tumors, and often, though not by any means inva- riably, proves of value. Various other forms of leucaemia have been treated with less success. The action of arsenic in reducing the glycogen of the liver suggested its use in diabetes, but most reliable authorities have failed to obtain satisfactory results. Arsenic has been used in some forms of trypano- soma infection in animals, and has been found to improve similar con- ditions in man. Arsenic is in the great majority of cases prescribed in the form of Fowler's solution. It is generally advisable to commence with small doses, and to increase them as tolerance is developed, but some au- thorities advise large doses from the outset. Arsenic is always pre- scribed to be taken after meals, in order to avoid any possible action on the digestion. 1 Several authors have recommended the hypodermic injection of Fowler's solution diluted with two parts of water. (Dose 0.5 c.c., 8 mins.) Arsenic is contraindicated in cases of irritation of the stomach and bowel, and is generally avoided during acute fever, except in malaria. If symptoms of chronic poisoning begin to assert themselves, the drug must be discontinued at once. The first symptoms are generally disordered digestion, loss of appetite and discomfort in the stomach region, a feeling of constriction in the throat and redness and swelling of the conjunctiva and eyelids. In Acute Arsenic Poisoning the stomach ought to be emptied at once by means of the stomach tube or by an emetic (apomorphine). The stomach washing is to be continued for some time, as arsenic is very insoluble. Iron or magnesium preparations have been advised in order to form a loose chemical combination with the arsenic ; freshly pre-r cipitated iron hydrate formed by adding magnesia to a solution of iron sulphate forms the well-known arsenic antidote, or magnesia alone is sometimes given shaken up with water. Experiments on animals 1 Cacodylate of sodium, in doses of 0.05 G. (1 gr. ), has recently been recom- mended as a substitute for the ordinary arsenical preparations. It appears to be ex- creted for the most part unchanged but a small percentage is reduced and this has the same effect as the more commonly used preparation (Heftier). ARSENIC. 619 show these antidotes are useless and that reliance is to be placed on repeated and copious lavage only. The collapse is treated by the ordinary measures, warmth and stimu- lants, such as caffeine and digitalis. In chronic poisoning, the paraly- sis is treated by stimulating the muscles with the galvanic current, the other symptoms by suitable general treatment. BIBLIOGRAPHY. A very complete account of the action of arsenic is given by Wertheimer in Richet's Dictionnaire de Physiologic, i., p. 674. Among the numberless papers on Arsenic the following may be mentioned : Boehm u. Unterberger. Arch. f. exp. Path. u. Pharm., ii., p. 89. Pistorius. Ibid., xvi., p. 188. Kossel. Ibid., y., p. 128. Gies. Ibid., viii., p. 175. Saikowsky. Virchow's Arch., xxxiv., p. 73. Falck. Arch. f. exp. Path. u. Pharm., vii., p. 394. Meyer. Ibid., xiv., p. 329. Filehne. Virchow's Arch., Ixxxiii., p. 1. Schulz u. Binz. Arch. f. exp. Path. u. Pharm., xi., p_p. 131, 200 ; xiii., p. 256 , xiv., p. 345; xv., p. 322 ; xxxvi., p. 275; xxxviii., p. 259 ; xli., p. 179. Husemann. Deutsch. med. Wpch., 1892, p. 1081. Lesser. Virchow's Arch., Ixxiii. and Ixxiv. Heffter. Arch. f. exp. Path. u. Pharm., xxxi., p. 257. Heinz. Virchow's Arch., cxxvi., p. 495. Wolkow. Ibid., cxxvii., p. 477. S.netana. Wien. klin. VVoch., 1897, p. 903. Engel. Virchow's Arch., cxxxv., p. 369. Selmi. Virchow-Hirsch. Jahsresber., 1881, i., p. 413. Tmbert-Gourbeyre. Des suites de 1'empoisonnement arsenical. Paris, 1881. Brouardel et Pouchet. Bull, de 1'acad. de med., 1889, p. 915. Dana. Brain, ix., p. 456. DaCosta. Phila. Med. Times, 1881, p. 385. Krehl Deutsch. Arch. f. klin. Med., xliv., p. 325. Kreyssig. Virchow's Arch., cii., p. 286. Huber. Ztschr. f. klin. Med., xiv., p. 444. Alexander. Habilitation-Thesis, Breslau, 1889. Erlicki u. Rybalkin. Arch. f. Psychiatrie, xxiii., p. 861. Busscher. Arch, internat. de Pharmacodyn., x., p. 415. Ringer and Murrell. Journ. of Physiol., i., p. 213. Nunn. Ibid., i., p. 247. Putnam. Boston Medical and Surgical Journ, cxx., p. 235. Bettmann. Ziegler's Beitnige, xxiii., p. 377. Loew. Pfliiger's Arch., xl., p. 444. Stockman and Greig. Journ. of Physiol., xxiii., p. 376. Journ. of Pathology, 1903. Geyer. Arch. f. Dermat. u. Syph., xliii., p. 221. Reynolds and others. Lancet and British Med. Journal, 1900, ii., and 1901, i. and ii. Morishima. Arch, internat. de Pharmacodyn., vii., p. 65. Heffter. Arch. f. exp. Path. u. Pharm., xlvi., p. 230. (Cacodylates.) Report of the Koyal Commission on Arsenical poisoning, 1903. On arseniuretted hydrogen. Staddmann. Arch. f. exp. Path. u. Pharm., xvi., p. 221. Minkowski u. Naunyn. Ibid., xxi., p. 14. Waechter. Vierteljahr. f. gericht. Med., xxviii., p. 251. PART IV. THE HEAVY METALS. HEAVY METALS. A LARGE number of important drugs, belonging to the chemical series of heavy nietals resemble each other so closely in their action in living organisms that they may be readily grouped together in a divi- sion of the pharmacological system. Some authors include in this series arsenic and antimony, but the former presents so many analogies to phosphorus in its eifects that it is preferable to treat it apart from the heavy metals. Antimony is certainly as closely related to arsenic as to this group, and may be regarded as a connecting link between them. The metals as such do not induce any symptoms except from their mechanical properties. Thus mercury may be swallowed in large quantities without causing mercurial poisoning, and silver or copper coins are equally devoid of effect as poisons. They are active only when they are capable of dissociation into ions of the metal or of an oxide. Thus potassium ferrocyanide does not cause any symptoms of iron poisoning when it is injected into a vein, because the iron passes through the body undissociated, and any eifects are due to the ferrocya- nide ion and not to the iron. In the same way compounds of the metals with ethyl and methyl, such as lead triethyl, have an action quite dif- ferent from that of lead, as long as they remain undecomposed in the tissues, but eventually induce metallic poisoning, as they are broken up into bodies from which the lead or lead oxide ion can be dissociated. The action of the heavy metals consists of two parts, the local effects induced at the point of application, and the general effects which fol- low the absorption of the poison into the blood and tissues. Either of these may be produced alone by suitable preparations and modes of administration, and they are to be regarded as entirely independent of each other. The Local Action of the heavy metal series is due to the formation of proteid combinations. When the salt of a heavy metal is added to a solution of egg albumin, or of similar proteid, a precipitate is at once formed of metallic albuminate. The proteids apparently play the role of acids, forming insoluble salts with the metals, but these salts are not generally of definite chemical composition, for the percentage of metal contained in the albuminate usually varies within wide limits ; in some cases, however, definite compounds have been formed. 621 622 THE HEAVY METALS. The albumin displaces the original acid of the salt, which may be entirely removed by prolonged washing. The albuminates of the metals are insoluble in water, but most of them are soluble in excess of proteid or of the metallic solution, and many of them may be dissolved in solutions of neutral salts such as chloride of sodium. In the albuminates formed by the addition of salts to proteid solutions, the metals are combined in the same way as in inorganic salts, and may be detected by their usual reactions. Thus iron albuminate is rapidly blackened by the presence of ammonium sulphide, because ferrous sul- phide is formed from it exactly as from any of the inorganic salts. On subjecting these albuminates to certain chemical manipulations, how- ever, the metal seems to become more firmly attached to the proteid, for ammonium sulphide acts on it much more slowly. The metal is then said to be masked, because its presence is not so readily detected as in ordinary combinations. Partially masked preparations have been formed artificially, but in the body the process is carried much further, for in many of their proteid compounds the metals cannot be detected by any of the ordinary tests, however long the reagents may remain in contact with them, and their presence is recognized only when the proteid is destroyed by heat or other similar agencies. When a solution of a metallic salt comes in contact with a living tissue, such as the mucous membrane of the mouth or stomach, the al- buminate is at once formed, and the acid with which the metal was combined is set free. The more completely dissociated the ions of the salt are, the more rapid is the reaction with proteid and the more in- tense the local action. Thus the more readily ionized inorganic salts act more strongly than the organic ones which are slowly dissociated, and these in turn are more liable to cause marked local changes than the double salts, which are dissociated with difficulty. 1 Other factors determining the nature of the local action are the character of the pre- cipitate and the activity of the acid formed, the latter again varying with the extent to which it is dissociated into ions ; it therefore exer- cises the same astringent or corrosive effects as if it had been applied uncombined, but its action may be modified by the presence of a layer of metallic albuminate protecting the surface. Thus when a weak solu- tion of lead acetate is applied to a mucous membrane, the metal forms an albuminate with the proteids lying on the surface and in the more superficial parts of the cells. This albuminate forms a continuous sheet over the mucous membrane, and the very dilute acetic acid formed is incapable of inducing any reaction. If a stronger solution be applied, however, the metallic precipitate extends more deeply into the cell, while the acetic acid, being more concentrated, exercises some irritant action. As the concentration increases, the deeper parts of the epi- thelial cells are coagulated, and at the same time the acid becomes more destructive, so that eventually the superficial layer of the epithelium is killed and the deeper layers are attacked. The acetate of lead may thus act as an astringent, covering a mucous surface with a protective 1 Paul. Bedeutung der lonentheorie f. d. physiol. Chemie, 1901, THE HEAVY METALS. 623 pellicle of insoluble albuminate, as an irritant, which induces an in- crease in the circulation of the part, a more rapid division of the cells and an effusion of liquid, or as a corrosive, involving the superficial layer of cells, and sometimes even the deeper ones in its destructive effects. When the nitrate of lead is applied, the astringent effect is much less evident, the irritant and corrosive more marked, because the salt is more readily dissociated and the reaction is therefore more rapid, and in addition the nitric acid is much more corrosive than acetic acid. The same metal attached to different acids may therefore induce very dif- ferent effects, in the one case acting chiefly as an astringent, in the other as an irritant and corrosive. The character of the precipitate formed also determines to some ex- tent the local action of the metallic salts. Thus the salts of mercury are more irritant and corrosive than those of the other metals, partly perhaps, because the precipitate is less continuous and more loose and flaky, partly because it is soluble in excess of proteid, and therefore allows the unattached molecules to penetrate deeply, while the lead albuminate remains on the surface of the membrane. The metals also differ in their toxicity, and a trace of mercury is sufficient to kill a cell, whereas a larger amount of lead may be absorbed by it without injury. In addition salts which have a very strong affinity for water with- draw fluid from the cells and thus act more strongly on them than others which have not this character ; for example dried alum is much more destructive to the tissues with which it comes in contact than alum containing its ordinary water of crystallization. The different metallic salts therefore vary in their local action within wide limits from the formation of mildly astringent mem- branes to the production of widespread necrosis and destruction of tissue. The insoluble salts come into less intimate contact with the tissues, and have much less effect ; but many of them are slowly formed into albuminates and may then act as irritants or astringents. The most powerful corrosive salts of any metal are those which are most rapidly dissociated into ions, that is, the chlorides and nitrates, provided they are soluble. The sulphates are much less irritant, be- cause they are less readily dissociated, and perhaps because the sul- phuric acid may fail to penetrate the cells owing to its being less volatile and its anion having less permeating power than that of hy- drochloric or nitric acid. (See page 535.) The iodides and bromides are generally regarded as less irritant than the chlorides, but are less frequently used and less well known. The least corrosive of the salts of the metals are those formed with the slowly dissociated organic acids, such as the acetates, tartrates or citrates. When these are united with a metal which in itself is not a very active poison, such as lead, they are almost purely astringent. On the other hand, the acetate of silver or of mercury tends to be irritant and corrosive, from the poisonous action of these metals on the 624 THE HEAVY METALS. tissues. In any case, the acetates are less irritant than the correspond- ing chlorides and nitrates, provided these are equally soluble. The local action also varies in the same salt of different metals. Lead is the most astringent of the metals ordinarily used in solution, while mercury salts have little or no astringent action, owing to their specific poisonous action on the cells. Iron and alum approach most nearly to lead, then copper, zinc and silver, and at a longer interval mercury. It is impossible to arrange the metallic salts as either astringents or irritants, because in every instance the effect varies with the concen- tration, and with many other features, such as the condition of the surface to which they are applied, and the quantity of proteid with which they come in contact before they actually reach the living mem- brane. Of the salts in common use the most astringent are lead acetate and alum ; the most irritant are the perchloride and the nitrate of mercury, the chlorides of zinc, copper, tin and antimony, while the chlorides of iron, sulphates of copper, zinc, iron and manganese, the acetates of copper and zinc and the nitrates of silver and lead are astringents when applied in very dilute solution, but tend to irritate and corrode in larger quantities. In most cases the effects of the last group are made up of a mixture of astringent and irritant action. The insoluble preparations of mercury tend to irritate and corrode the surfaces to which they are applied, but the insoluble salts of the other metals are generally astringent. It is difficult to determine how far the so-called astringent and protective action of these insoluble substances is due to the formation of albuminates, and how far to their acting mechanically as protective coverings over irritated surfaces, but the latter factor is undoubtedly the more important in many instances. The precipitation induced by the astringents involves only the surface layer of cells, but the membrane formed protects the part from me- chanical and chemical irritation, and thus lessens congestion and inflam- mation. In addition several authors l have found that the astringent salts contract the vessels of the frog's mesentery by direct action on their coats, and have inferred that the same constriction is induced in the mucous membranes, when they are applied to them. Schiitz 2 found that the secretion of the frog's skin and tongue is lessened when these parts are washed with astringent metallic salts, and it is quite possible that when these are applied to inflamed membranes, they may constrict the vessels and lessen the secretions, as well as form a protective membrane. When irritation is induced, the vessels of course dilate, and congestion and exudation follow. The local action is due to the formation of albuminate compounds and the liberation of acid. If the metal be applied in the form of an albuminate, this irritation is almost entirely absent except in so far as l Eosenstirn, Eossbach's Pharmakologische Untersuchungen, ii., p. 84. Hei-nz, Vir- chow's Arch., cxvi., p. 220. 2 Arch. f. exp. Path. u. Pharm., xxvii., p. 202, THE HEAVY METALS. 625 the poisonous action of the metal may cause necrosis and consequent irritation and inflammation. The double salts of the metals are also less liable to irritate, because they do not precipitate albumin, and their dissociation only occurs slowly and is not confined to the point of application. Of course if these double salts are decomposed by acids, as in the stomach, they may act as irritants. The salts of the heavy metals are often only slowly Absorbed. Mercury is again an exception, but even mercury does not induce gen- eral symptoms until many hours after its administration. The other metals given by the mouth pass through the alimentary canal for the most part unabsorbed. In recent years it has been disputed whether iron, manganese, copper and other metals are absorbed at all, but investigation with more accurate methods has shown that iron and manganese pass into the tissues from the alimentary tract, and it seems probable that a small proportion of most of the metals finds its way into the blood. At the same time there is no question that the great pro- portion of most of the metals passes through unabsorbed, and is devoid of any effect except from its local action. It is probable that the small quantity taken up by the stomach and intestine is first formed into proteid compounds in every instance, but there is very little known as to the process. When there is any lesion of the stomach and intestine, and particularly when the salt induces irritation and con- gestion itself, much more of the metal is taken up than by the normal epithelium. But even in the most favorable circumstances little of the metal is absorbed, and in acute poisoning the symptoms arise from the local irritation and corrosion, and only to a smaller extent from the general action of the metal. If the absorption of the metals is slow, their Excretion progresses even more gradually, and repeated administration leads to their accum- ulation in the tissues and thus to intoxication. The metal seems to leave the blood very rapidly, and to become stored up in various organs, chiefly the liver, to a less extent the spleen, kidney, and bone marrow. While some of the metal is deposited in the liver and other organs, another part is excreted, for the most part along the alimentary tract. Thus it is found in the saliva and gastric secretion, to a much larger amount generally in that of the lower parts of the small intes- tine, in the ca3cuni and in the large bowel. A comparatively small amount escapes with the urine. Some metals have been detected in very small quantity in the milk, and there is reason to suppose that traces are eliminated by the other cutaneous secretions. The General Action of the heavy metals in man is often elicited only by their prolonged ingestion, but it has been studied in animals by the intravenous or subcutaneous injection of the albuminates or of the double salts, which do not precipitate the proteids. The ordinary salts cannot be used, because the precipitated albumin of the blood causes embolism, and this obscures the symptoms. The symptoms of acute metallic poisoning elicited thus in animals generally resemble fairly closely those of chronic poisoning in man. Of course the ana- 40 626 THE HEA VY METALS. tomical lesions induced in the latter by the constant presence of small quantities of metals in the nutritive fluids, can only be induced to a limited extent in such experiments. Even when the heavy metals are injected into the blood in consid- erable quantity, the symptoms are often late in appearing, in the case of aluminium only after several days, so that the slowness of the ab- sorption from the intestine is not the only explanation of the delay in the onset of the intoxication. The general symptoms of metallic poisoning, as distinguished from those due to the local action at the point of application, arise chiefly from the central nervous system, and from the excretory passages the alimentary canal and the kidney. Metallic poisoning always in- duces disturbance of the Stomach and Intestine, manifested by loss of appetite, pain and discomfort in the abdomen, nausea, vomiting and purging. In some cases no lesion of the canal is observed post mortem, but in the great majority congestion and swelling of the mucous mem- branes of the stomach and intestine is seen, or the whole surface may be covered by a diphtheritic membrane composed of necrosed cells and inflammatory exudate. Beneath this haemorrhages occur, and if the animal live long enough, ulcers are formed, so that the whole con- dition can scarcely be distinguished from that of dysentery. Some metals act strongly on the mouth and salivary glands, salivation being one of the earliest features of mercury poisoning. The lining mem- brane of the mouth becomes congested and inflamed, and numerous shallow ulcers are formed in it. The heavy metals thus seem to have a specific action along the alimentary tract quite independent of the local action induced when they are swallowed. This is connected with their excretions along it, although it seems inadvisable in the present state of knowledge to say that they irritate the digestive tract because they are excreted in it. One or two metals, notably lead, cause constipation and colic when they are absorbed into the blood, but under certain circumstances they too induce purgation. Another organ which suffers from the circulation of metals in the blood is the Kidney. Comparatively little of the metal is excreted in the urine, but it is found that most of this class act as diuretics in small quantities. Somewhat larger doses irritate the renal epithelium, and albumin appears in the urine, along with casts and in severe cases blood cells and haemoglobin. If this irritation of the secretory cells be long continued, it sets up a secondary inflammation of the intersti- tial tissue, and cirrhosis of the kidney results. The Circulation is differently affected by different metals, or at any rate, the effects on the heart and vessels are described differently by the writers on the subject. Very often the heart is affected only in the last stages of poisoning, and it is impossible to determine how far its failure is due to direct action, and how far to the general disorder of the nutrition. The blood-pressure invariably falls towards the fatal issue of the intoxication, and as a general rule, a slow fell is THE HEAVY METALS. 627 observed from the beginning. This fall in blood-pressure has been ascribed to the heart action, to depression of the vaso-motor centre, and to paralysis of the splanchnic terminations in the mesenteric ves- sels. It may doubtless be induced by different factors in the different forms of intoxication, but there is no question that it is partly due to the dilatation of the vessels of the intestines and stomach from the inflammation of these organs. Several metals have been found to lessen the alkalinity of the Blood by increasing the amount of lactic acid in it, but this does not seem a common feature in metallic poisoning. The general malnutrition from the gastro-intestinal action renders it impossible to determine whether the metals alter the metabolism of the body through directly affecting the cells, but it is not improbable that this is the case, for the loss of weight is often too rapid to be explained by the starvation alone. The Central Nervous System is always affected more or less by the presence of the metals in the blood. As a general rule, the symptoms are a mixture of those of stimulation of certain divisions with those of paralysis of others. Several metals induce disturbance of the psychical centres, manifested in delirium, hallucinations and mania, or in stupor and coma. Convulsions of all forms indicate that the motor areas of the brain, the basal ganglia and the spinal cord are affected; thus epileptiform convulsions, chorea, clonic and tonic spasms occur from metallic poisoning. In several instances actual lesions of the brain cells have been shown to be caused by the ingestion of the metals. They often cause general weakness, or paresis of certain groups of muscles, and in addition to their specific action on the nervous centres, they may induce a peripheral neuritis (lead). The muscles do not seem to be so readily affected in general poisoning, although a solution of a non-irritating metallic salt generally paralyzes muscles suspended in it. Therapeutic Uses. In therapeutics only mercury and iron are largely employed for their effects after absorption, while the others have a more or less extensive use for their local effects as astringents, irritants, caustics or styptics. Iron is not prescribed for its general action on the organs, but to supply the place of food-irons in the formation of hae- moglobin. Mercury is used for its specific effect in syphilis, and some of its preparations have been advised as diuretics. Not infrequently the local action of the heavy metals is supposed to be induced after ab- sorption, and prescriptions are met with containing lead or iron which are intended to stay haemorrhage from the lungs or from the kidneys. It ought to be recognized, however, that lead or iron is absorbed only in minute quantities, and that they have no predilection for the bleed- ing points. If they were capable of coagulating the blood after ab- sorption, and thus stopping haemorrhage, they would certainly do so in the portal circulation and would not be carried to the lungs or kidney before they acted. As a matter of fact, however, they never reach the blood except in forms in which they have no astringent or styptic action. 628 THE HE A VY METALS. Many of the metallic salts are powerful antiseptics, partly no doubt from their coagulating the proteids of the microbes, but also from a specific poisonous action on them, which is quite distinct from their precipitating action. As a general rule the antiseptic power varies with the amount of dissociation of the salt, that is, with the number of metallic ions present in the solutions, although the undissociated mole- cule also seems to have some influence, and a salt which is dissociated with difficulty may in some instances make up for this drawback by the more intense toxicity of the metal. 1 The most widely used metallic antiseptics are the mercurial salts, in particular the perchloride, but other metals have recently begun to play a more important role in sur- gery than heretofore. Almost incredibly small quantities of some of the metals have been found to be rapidly fatal to some of the algae, the bacteria, and the infusoria. Thus one part of the perchloride of mer- cury in one million parts of water kills spirogyra, one of the simpler algfe, and water distilled from copper vessels is rapidly destructive to it. Israel and Klingmann 2 hung small pieces of copper foil in water for a few hours, and then diluted this water a hundred times and found it still poisonous to many lower organisms. Silver was less active and lead still less so. The amount of copper in the original solution was too small to be recognized by any chemical test, much more so then in the further diluted portion. These results, which were first obtained by Naegeli, and which have been confirmed by other observers besides Israel and Klingmann, indicate that certain lower organisms are much more sensitive to the action of copper, and probably of other metals, than the more highly organized plants and animals. Further exami- nation of their effects as antiseptics in medicine and surgery is certainly desirable. Other curious effects on the growth of bacteria have been ob- served by Bolton and Brown, 3 who found that a piece of metal placed on a culture of microbes in gelatin causes curious alternating zones of intense growth and of sterility. These observations have recently been extended by Thiele and Wolff, 4 who state that silver, mercury and copper plates prevent the growth of microbes owing to minute traces of these metals being dissolved in the medium. Several other heavy metals iron, lead, zinc, tin, gold, platinum and aluminum proved devoid of action. A practical application of this bactericidal action of the metals has been made by the introduction of solutions of colloid forms of silver and mercury as antiseptics. Some of these colloid metals have proved destructive to simple organisms in extremely dilute solution, while in more concentrated forms they are inferior to the ordinary salts of the metals. 1 Kronlg u. Paul. Ztschr. f. Hygiene, xxv., p. 1. 2 Virchow's Arch., cxlvii., p. 293. 3 Transactions of the Assoc. of Araer. Physicians, xii., p. 488. 4 Arch. f. Hygiene, xxxiv., p. 43. ANTIMONY. 629 I. ANTIMONY. The preparations of antimony played a much more important role in therapeutics in the earlier part of last century than at the present time, and promise to be used to a still more limited extent in the future. In many respects they resemble arsenic in their effects, and may be looked upon as forming a link between it and the salts of the other heavy metals. The salt most commonly used is tartar emetic, or the double tartrate of antimony and potassium [K(SbO)C 4 H 4 O 6 ] . The effects of this salt were at one time believed to be due in part to the potassium, but have been shown to be those of the antimony alone. Many other compounds of antimony have been used in therapeutics, and several others are still found in the pharmacopoeias, but they differ for most part from tartar emetic only in the rapidity of their action. Tartar emetic, like other double salts, is not corrosive, because it does not precipitate proteids except in acid solutions, in which it is decomposed into simpler forms. The chloride of antimony, on the other hand, readily dissociates the antimony ion and is a powerful caustic when applied to the skin or the mucous membranes. When rubbed on the Skin, however, tartar emetic causes redness, and a papular eruption, which later passes into vesicles and pustules. If the application be further persisted in, these pustules may become confluent and form small abscesses, and later cause extensive necrosis and ulceration of the skin. The points of origin of the papules are the openings of the cutaneous glands and the hair follicles. Symptoms. Tartar emetic has a slight, acrid taste, and in very small quantities causes no symptoms, except some perspiration. In somewhat larger doses its ingestion is followed by nausea and vomiting, with very marked depression and the usual accompaniments of emesis, such as salivation, profuse perspiration and acceleration of the pulse (see Apomorphine, page 235). In antimonial poisoning the vomiting is violent and continuous, the ordinary contents of the stomach being first evacuated, and then a slimy mucous fluid, which may later con- tain blood. In some cases it is said that no gastric symptoms are observed, but these must be exceedingly rare. The vomiting is ac- companied by profuse watery diarrhoea, resembling that of arsenical poisoning, and by great muscular weakness and collapse. The pulse may be somewhat accelerated at first, but is weak, and later becomes slow and irregular. The skin is cold and covered with a clammy per- spiration, and cyanosis of the face and extremities is generally marked. The respiration is slow and may be irregular, the voice weak and husky, the temperature is depressed, and the patient falls into a coma- tose condition, which deepens, until after a few weak convulsive move- ments the respiration ceases. The urine is sometimes increased in the beginning of the poisoning, but later may become scanty or entirely suppressed. It often contains albumin. The minimum fatal dose of tartar emetic is doubtful, as the greater part of the poison is generally removed by vomiting. Recovery has 630 THE HEA VY METALS. been observed after very large quantities, while in other cases 0.1 G. (2 grs.) has proved fatal. Chronic antimonial poisoning is very rare and difficult to diagnose. The symptoms are depression, headache, giddiness and confusion, drowsiness and indistinct sight. The appetite is bad, and the patient complains of heavi- ness, discomfort, or pain in the region of the stomach, general weakness and exhaustion. Profuse diarrhoea may be present, rapid loss of flesh, albumi- nuria and finally collapse. Pustular eruptions have been observed from the prolonged internal use of tartar emetic. Action, Many of the symptoms of antimonial poisoning, the pro- fuse perspiration, salivation and, to some extent at least, the collapse, are manifestly secondary to the Emetic Action, and the cause of the vomiting has, accordingly, been repeatedly investigated. It may be stated at once that some authors attribute the vomiting to a central action, but that the majority are inclined to regard it as mainly due to irritation of the stomach. Large doses of antimony affect the stomach and bowel in the same way as arsenic, inducing hypersemia and swell- ing and loosening of the epithelium, but smaller quantities such as are used in therapeutics do not seem to cause any obvious lesion- It is found that tartar emetic injected hypodermically or intravenously causes nausea and vomiting, but much larger quantities are required than are requisite when the drug is given by the mouth. This indi- cates a direct action on the stomach, rather than on the centre for vomiting, and this view is supported by the fact that antimony is found in the stomach and intestine when it is injected intravenously. The obvious explanation would therefore seem to be that antimony given by the mouth acts as a gastric irritant, and causes vomiting, while when it is injected intravenously it is carried to the stomach, and again causes irritation with the same result. The whole of the antimony swallowed acts at once on the stomach, while only a part of that injected exerts its action on it, and larger doses are therefore necessary when the poison is administered in the latter way. This explanation is opposed, however, to an observation made by Orfila, who found that when the stomach was excised and replaced by a dead blad- der, tartar emetic still caused the movements of vomiting, which even expressed the fluid in the bladder. Of course no antimony could be excreted into the bladder, and no irritation or reflexes could arise from it. Again Mosso states that when the vagus nerves are cut below the diaphragm, tar- tar emetic fails to cause vomiting when it is swallowed, but large doses have their usual effect when injected into a vein. These observations appear at first sight to indicate that tartar emetic acts centrally, but it has been sug- gested that although the poison could not act on the stomach in Orfila' s experiment it might cause vomiting by causing irritation of some other part of the alimentary tract. As regards Mosso' s results, the relation of the vagus nerve to vomiting is still so obscure that it is dangerous to draw any inference from such experiments. On the whole the evidence goes to show that the emesis is due to irritation of the gastric mucous membrane by the antimony. The action of tartar emetic on the Stomach has been explained by supposing that the acid gastric juice decomposes the double salt and ANTIMONY. 631 that the chloride thus formed acts as a corrosive in the same way as the chlorides of the other heavy metals. This, however, fails to ex- plain the fact that the same effects are met with in the intestine, in which no such acid fluid exists, and that vomiting is induced readily when the gastric juice is neutral in reaction (Mosso). A more prob- able explanation is that antimony has a specific irritant effect on the mucous membranes of the stomach and bowel, similar to that of ar- senic. The irritation is greater, however, and is induced more rapidly, so that vomiting is caused much more easily. At the same time, an- timony is more slowly absorbed than arsenic, so that its action re- mains confined to the stomach, and as the vomiting removes much the greater part of the poison, the intestine remains unharmed except when large quantities have been swallowed and the emesis is from any cause insufficient. In chronic poisoning ulceration of the small intes- tine is said to occur, especially around the solitary follicles and Pey- er*s patches. The acceleration of the Pulse seen after tartar emetic is due for the most part to the emetic action and not to the absorption of the drug. When in- jected into a vein in animals, antimony causes a slow and weak pulse, although this is preceded in some cases by slight acceleration. The action is a direct one on the cardiac muscle, as maybe seen by perfusing an excised frog's heart with blood containing some tartar emetic. The cardiac nerves do not seem to be affected. The Blood-pressure falls throughout the experiment, partly owing to the weakness of the heart but chiefly owing to an action on the vascular mecha- nism similar to that described under arsenic. Here again it is doubtful whether the effect is due to the vaso-motor centre or to the peripheral nerves and muscle of the vessels, but the latter are certainly involved, for stimula- tion of the spinal cord fails to contract the mesenteric vessels. The Respiration is often slightly accelerated at first, and may be shallow and irregular from the nausea ; but in cases of poisoning it becomes slow and labored, and eventually ceases along with the heart. The respiratory centre is perhaps affected directly to some extent, but the changes in the breathing are probably due for the most part to the disturbance of the circulation, and to the action on the alimentary canal. The statement made by some of the older writers that antimony caused hepatization of the lungs, has been shown to be incorrect. The Central Nervous System is depressed by antimony in the frog, spontaneous movements persisting after the reflexes have disappeared, according to some authors. This has been interpreted to mean that antimony paralyzes the sensory part of the cord or its connection with the motor cell, while leaving the connections between the latter and the brain intact ; but the statement itself requires further confirmation. The paralysis is due to the direct action of antimony on the nerve cells and not to the disordered circulation, for frogs poisoned with antimony are paralyzed sooner than others in which the circulation is entirely destroyed by the excision of the heart. The effect of antimony on the central nervous system of the mammals is more obscure, for it is impossible to ascertain how far the changes are due to direct action and how far they are attributable to the disturbance of the circulation and the alimentary canal. There is reason to believe, however, that the poison depresses to some extent the nerve cells here also. Accord- ing to Schaffer, the cells of the spinal cord undergo a degeneration marked by the disappearance of the chromatin in chronic antimonial poisoning. 632 THE HEA VY METALS. The Depression and Collapse of antimony poisoning are caused by the gastric effects and the slowed circulation acting on the central nervous sys- tem, and not, as is sometimes stated, to the peripheral nerves and muscles being affected. The voluntary muscular tissue is undoubtedly weakened to some extent in the frog, but only after large doses and at a late stage. The muscles then contract somewhat more weakly than normally, and are more readily fatigued. Many of the Secretions are increased by tartar emetic, such as the per- spiration, the saliva and the mucous secretion of the respiratory tract. This is not due to any direct action on the glands, for the same effect is induced by anything which causes vomiting. (See Apomorphine, page 235.) The urine is sometimes increased by antimony, at other times it is diminished or suppressed. This is perhaps due to a preliminary stimulation of the renal epithelium, which passes into acute irritation when much of the drug is ab- sorbed. The action on the urinary secretion is not very marked, however. The irritant action of tartar emetic on the Skin when it is applied to it in ointment, has been explained by the double salt being broken up by the acid formed in the decomposing secretions, and an analogy has been drawn between it and the irritant effects in the stomach. In support of this it is said that the addition of alkalies to the tartar emetic ointment prevents the formation of pustules. This does not seem a very happy explanation, although it accounts for the formation of pustules at the openings of the skin glands. The double salts of other metals, however, which would form irritants in the same way as tartar emetic have no special effect on the mouths of the gland ducts. Nunn finds a specific effect on the skin of the frog when tartar emetic is injected, similar to that induced by arsenic, but more rapid in its onset, and this may explain the pustulant action. A pustular erup- tion is said to be induced in some cases when antimony is taken internally. Pustules also occur in the oesophagus when tartar emetic is swallowed, and irritation of the mouth and swelling of the lips have been observed. The effects of antimony on the Nutrition have not been so carefully examined as those of arsenic, but, as far as is known, present a strong re- semblance to them. Thus fatty degeneration of many organs is induced by its prolonged use, the nitrogen of the urine is found to be increased, and the glycogen disappears from the liver. Very small quantities of antimony given repeatedly are said to increase the glycogen and fat of the liver, with- out apparently altering the nitrogen of the urine. The fall in Temperature after antimony is often very considerable, amount- ing in animals to 6 C. in the course of a few hours. It is explained by the slowness of the circulation and by the general depression and collapse and profuse perspiration. Antimony is Absorbed from the skin very slowly, and from the stomach and intestine. It passes into the tissues much more gradually than arsenic, however, and its action on the stomach, can, therefore, be elicited without danger of its causing general symptoms. After absorption antimony is found in considerable quantity in the liver, which stores it up for some time. It is excreted into the stomach and intestine, in the urine, and, it is said, in the bile and milk. The Chloride of Antimony (SbCl,) differs from tartar emetic chiefly in being a violent corrosive, which combines to form albuminates and thus acts like ANTIMONY. 633 the other salts of the heavy metals, and also tends to withdraw fluid from the superficial tissues, when it is applied in a concentrated solution. The other compounds of antimony act like the double tartrate, except that most of them are much slower in their effects. Stibine or antinioniuretted hydrogen (SbH 3 ) differs entirely from arsine (AsH 3 ) in its action, which is, however, equally poisonous. It has very rarely been examined, except in an impure form, and the symptoms are imperfectly known. PREPARATIONS. ANTIMONII ET POTASSII TARTRAS (U. S. P.), ANTTMONIUM TARTARATUM (B. P.), tartar emetic, tartarated antimony ((KSbOC 4 H 4 O 6 ) 2 -f H 2 O) forms colorless, transparent crystals, or a white granulated powder, without odor, and having a sweet, afterwards disagreeable, metallic taste, soluble in 17 parts of cold water, insoluble in alcohol. Dose as a diaphoretic 0.002-0.008 G. (jV-i- gr.), as an emetic 0.03-0.1 G. Q-2 gr.). VINTJM ANTIMONII (U. S. P.), VINUM ANTIMONIALE (B. P.), 4 parts of tartar emetic in one thousand (U. S. P.), in 875 parts (B. P.). 0.6-2 c.c. (10-30 mins.), diaphoretic ; 4-15 c.c. (1-4 drs.), emetic. Tartar emetic is also contained in the compound syrup of squills U. S. P. Antimonii Oxidum (B. P.), (Sb 2 O 3 ), a heavy, gray, insoluble and tasteless powder. 0.05-0.1 G. (1-2 grs.). Pulvis Antimonialis (B. P.), James' powder, consists of antimony oxide 1 part to 2 parts of phosphate of calcium. 0.15-0.3 G. (3-6 grs.). Antimoniwm Nig rum Piirificatum (B. P.) (Sb 2 S 3 ), a heavy grayish-black powder, odorless, tasteless, and insoluble in water. 0.015-0.06 G. Q-l gr.). Antimonium Sulphuratum (B. P.), Kermes mineral, consists of antimony sul- phide (Sb 2 S 3 ) with a small amount of oxide (Sb 2 3 ) an amorphous, reddish-brown powder, odorless, tasteless, and insoluble in water. 0.06-0.3 G. (1-5 grs.). Pilula Hydrargyri Subchloridi Composita (B. P.), Plummer's Pills, compound calomel pill, 8 grains contain nearly 2 grains each of calomel and of sul- phurated antimony. 4-8 grs. Therapeutic Uses. Antimony is used to a much less extent in med- icine than was formerly the case. In the seventeenth century it was prescribed so widely and was believed to do so much harm, that the graduates in medicine of Heidelberg were required to take an oath never to use it. At present it is used to a limited extent as an emetic, but is slow in action and induces greater depression and more pro- longed nausea than the other drugs which are prescribed for this pur- pose, such as apomorphine, ipecacuanha, or sulphate of copper. It is therefore seldom used to evacuate the stomach in cases of poisoning or of foreign bodies in the stomach or oesophagus. Its expectorant action is taken advantage of in acute bronchitis in which the secretion of the bronchial mucous membrane is insufficient, but it is of less value when the secretion is abundant. In commencing bronchitis tartar emetic is sometimes given until vomiting occurs, and then continued in smaller doses and at longer intervals. It is also used as a diaphoretic to some extent, in the same doses as are prescribed as expectorants, but it has been almost entirely supplanted by pilocarpine for this purpose. James' powder was especially popular as a diaphoretic, but is now seldom employed. In acute fever antimony was formerly largely used as a depressant, more especially when delirium was a marked feature. The object was to produce 634 THE HEAVY METALS. a mild collapse, but the treatment has been entirely abandoned by most authorities, and probably did more harm than good. Acute lobar pneu- monia was almost universally treated by tartar emetic at one time, and an attempt has recently been made to revive this treatment, but without suc- cess. Antimony has been advised instead of arsenic in the internal treatment of skin disease, but it is impossible to state at present how far it is capable of replacing the more widely used drug. In all cases in which there is marked depression or weakness, in which the stomach or bowel is disordered, or in which the circulation is feeble, the preparations of antimony are contraindicated. Tartar emetic was formerly used in ointment (one part to four) as a skin irritant, but its continued application has led in several cases to diffuse sub- cutaneous abscess, and sometimes to necrosis of bone, so that the tartar emetic ointment has passed into desuetude. In cases of Antimonial Poisoning, emetics are seldom required, but the stomach may be washed out by means of the stomach tube, if vomiting is not present, and a purge may be given to remove the poison in the bowel. Tannic acid is used to precipitate the antimony in the stomach, and the tannate formed must be washed out. A form of tan- nic acid which is usually available in emergencies is strong tea, which is also useful as a stimulant for the collapse. Lime or magnesia may be used to precipitate the antimony instead of tannic acid. BIBLIOGRAPHY. Ackermann. Virchow's Arch., xxv., p. 531. Radziejewski. Arch. f. Anat. u. Phys., 1871, p. 472. Saikowski. Virchow's Arch., xxxiv., p. 73. Soloweitschyk. Arch. f. exp. Path. u. Pharm., xii., p. 438. Kobert. Ibid., xv., p. 36. Grimm. Pfliiger's Arch., iv., p. 205. Harnack. Munch, med. Woch., 1892, p. 179. Ringer and Murrell. Journ. of Physiol., i. p. 241. Stock and Guttmann. Ber. d. deutsch. chem. Gesell., xxxvii., p. 884. Thumas. Virchow's Arch., cxxiii., p. 66. Mosso. Schmidt's Jahrbuch, clxix., p. 236. Chittenden and Blake. Studies from the Lab. of Physiolog. Chem. Sheffield Scientific School, ii., p. 87; iii., p. 106. Kubeler. Arch. f. exp. Path. u. Pharm., xxvii., p. 451. II. MERCURY. Mercury, one of the most powerful inorganic poisons, has been used in medicine for a long time and in a large variety of forms. Some differences are observed in the action of these, but all of them induce the same general results, the differences existing only in their local effects, and being due to the salts differing in solubility and dissocia- bility. A soluble salt, such as the perchloride, comes into more inti- mate contact with the tissues, and therefore acts more powerfully locally, and is also absorbed more rapidly and in larger amount than calomel, which is entirely insoluble in water. Both the local and the general effects of the perchloride are more marked than those of calo- MERCURY. 635 mel, therefore, but when sufficient mercury in the form of calomel is absorbed into the tissues, the general effects are the same as if an equal quantity had been taken up as perchloride. Mercury is absorbed and circulates in the blood in the form of the albuminate, which is insoluble in water, but is rendered soluble by ex- cess of proteid, and also by chloride of sodium in such quantities as are met with in the tissues. The solubility of the albuminate ex- plains how mercury is absorbed so much more quickly than any of the other heavy metals, and at the same time it may account .in part for its greater corrosive action. The corrosion is due to some extent to the acid constituent of the preparation, but this is not greater than that of an equally soluble and equally dissociable combination of the acid with another metal. The mercurial ion itself is also corrosive, and its de- structive action is the more powerful because the precipitate formed with proteids is less insoluble in the surrounding fluids of the body and is therefore more flocculent and affords less protection to the surface, than those formed by the other heavy metals. The mercurial action is consequently not limited to the surface of a tissue but extends into the deeper cells. The highly corrosive action of the mercury ion has been ascribed to its great affinity for the amido-cornpounds which are con- tained in the albumin molecule. Liebermann has also shown that it has a special affinity for lecithalbumin, and it is possible that this may play an important role both in the absorption and in the slow excretion of the metal. The albuminate is formed rapidly when such soluble salts as the perchloride come in contact with the tissues, and the local corrosion is greater and the absorption more rapid than when an insoluble salt is ingested. A good deal of dispute has arisen as to the absorption of the insoluble salts of mercury, and it is frequently stated that calomel is first changed to the perchloride by the action of the hydrochloric acid of the stomach and by the chlorides of the tissues, and that only then is the albuminate formed. There is, however, no sufficient evidence that the perchloride is formed from the chloride, and such a change is not necessary to explain its absorption, for the proteids of the tissues can act on calomel as such, and, forming the soluble albuminate, allow it to be absorbed. It has been asserted of late that when calomel is injected hypodermically, the leucocytes take it up and carry it off as they do any other foreign insoluble body, and it is quite possible that they may take it up in the same way from the alimentary canal. At the same time the quantity of calomel which comes into intimate con- tact with the tissues is much smaller than in the case of the soluble perchloride, and a smaller proportion of calomel is absorbed therefore. In the same way other insoluble preparations of mercury are absorbed in the form of aibuminates, and even the metal may be oxidized and absorbed when it is applied to the living surfaces or injected into the blood in a state of fine division. Thus the inhalation of mercury vapor by the lungs leads to general poisoning, often of a very malignant type, and mercury rubbed into very fine globules, and applied in ointment 636 THE HEAVY METALS. to the skin, passes into the gland ducts and along the roots of the hairs, and, after being oxidized, is dissolved and absorbed into the tissues, in which it causes the typical mercurial effects. Symptoms. Acute Mercurial Poisoning occurs only from the use of soluble preparations, and in particular from the perchloride of mercury or corrosive sublimate. Many cases have arisen from this poison being swallowed accidentally or with suicidal intent, but of late years an almost equal number has arisen from the perchloride being used as an antiseptic wash for large cavities. When corrosive sublimate is swal- lowed in poisonous quantity, the patient complains at once of the harsh, metallic taste, which is followed by burning pain in the mouth, throat and stomach. Nausea and vomiting set in very soon, and the vomited matter may contain shreds of mucous membrane and blood. Diar- rhoea and violent tenesmus, with watery or bloody stools, often con- taining shreds of membrane, may be among the early symptoms, or may only occur after twenty-four hours. These symptoms from the alimentary canal are accompanied by collapse, with a small, thready, sometimes irregular pulse, shallow, irregular, rapid respiration, cold, clammy skin, pinched features, and sunken eyes. The temperature is often subnormal, but sometimes fever is observed, although this is attributed by many to concurrent disease. The consciousness is usually unaffected, but in some cases somnolence, giddiness, or more rarely anxiety and restlessness have been observed. The urine is much diminished and complete anuria often occurs in a few hours. If the urine is not completely suppressed, it generally contains albumin, renal epithelium, casts, and more rarely sugar. Death may occur within an hour from shock, but more frequently the patient survives several days or even one or two weeks, the symptoms of intestinal corrosion and of renal irritation continuing, until he finally sinks from exhaustion. When acute poisoning occurs from the absorption of corrosive subli- mate from wounds, the symptoms of corrosion of the mouth and stomach are absent at first, but the dysenteric symptoms and the renal inflam- mation are produced in the same way as when the poison is swallowed. Here again the patient may die within a few hours, but more fre- quently survives for several days, and in the latter case the symptoms towards the end partake of the character of chronic poisoning. In particular, salivation and stomatitis set in in the course of a few days. These also occur when the poison is swallowed, although they are more liable to be overlooked, from the cauterization produced in the mouth by the local action. Chronic Poisoning. A much more frequently observed form of poisoning is that induced by the prolonged medicinal use of mercury. It may arise from any of the preparations, and from any form of ap- plication, although some methods of administration are credited with being less liable to induce it than others. Thus inunction with mer- curial ointment and the use of calomel internally are both more liable to cause the severer forms of stomatitis than is corrosive sublimate. A single hypodermic injection of an insoluble preparation may induce MERCURY. 637 it in susceptible persons, because the mercury is only slowly absorbed, and passes into the tissues as gradually as if it were given by the mouth regularly for several days. This chronic poisoning or Mercurialism is due, not to the local action, but to the effects of the drug after absorp- tion. It is much more liable to occur in certain people than in others, but may follow the abuse of mercury in any case, and the cause of the abnormal susceptibility to mercury is unknown. When mercurialism begins to be manifested, the drug ought to be stopped, or the dose much reduced, until the symptoms disappear. Formerly it was be- lieved that the earlier symptoms of mercurial poisoning had to be in- duced in the cure of syphilis, but in modern therapeutics every effort is made to avoid them. The first symptoms generally arise from the mouth and throat, the patient complaining of a metallic taste, and of a feeling of numbness or soreness of the tongue and gums. The breath has an unpleasant fetid odor, the tongue is swollen and thickly coated, the gums are soft, swollen and often of a dark bluish-red or gray color and the flow of saliva is augmented. If the medication be continued as was often done formerly, ulcers appear on the gums and on the sides of the tongue where it comes in contact with the teeth, especially if these are carious, and on the mucous membrane of the cheeks ; the salivation increases and irritates the lips and the skin where it is exposed to the secretion. If the administration of mercury be still persisted in, the teeth become loose and fall out, gangrene of the gums, lips and throat, and necrosis of part or even of the whole jaw may follow, and may prove fatal by exhaustion and inanition due to the difficulty in swallowing and to the complete absence of desire for food. The milder forms of stomatitis and salivation are observed in a large proportion of cases of syphilis treated with mercury, according to some authors in 30 per cent, or more. It may be avoided, to some extent, at least, by scrupulous cleanliness of the mouth and teeth, by the filling of carious teeth, and by using a 2-4 per cent, solution of chlorate of potash as a mouth wash. The stomach and intestine also suffer in chronic mercury poisoning. The patient often complains of loss of appetite, and occasionally of a feeling of weight and discomfort in the stomach, nausea and vomiting, general weakness and loss of flesh. Colic and diarrhoea are frequently observed, or diarrhoea and constipation may alternate. These symp- toms are naturally more liable to occur from the administration of mercury by the mouth than by other channels, as here the action after absorption is reinforced by the direct local effects. Some fever is sometimes noted, but this is secondary to the affection of the mouth, bowel or skin, and is not directly attributable to the mercury. Occasionally skin eruptions are seen when mercury is given by the mouth, but much more frequently when it is applied to the skin. In the latter case they are not limited to the point of application, although they often begin from it and spread over a large surface of the body. They are said to occur often without any other symptom of poisoning, except the fever and discomfort which they induce themselves. They 638 THE HEAVY METALS. vary greatly in form, consisting of small reddish spots, large red ery- thematous surfaces, urticaria, or eczema, each of these occurring alone or in succession, and being usually followed by desquamation. The eruption generally lasts only 1-3 weeks, but in some cases has not en- tirely disappeared until three months after its first appearance, and in others has returned repeatedly afterwards. It is said to have been induced occasionally by a single dose of calomel. The urine is often somewhat increased, but may be decreased after- wards, and it not infrequently contains albumin, although the proportion of cases in which this occurs is much disputed, and the amount in the urine is generally very small. Glycosuria is much rarer in man, but has been frequently observed in rabbits after prolonged treatment with mercury. It is still a matter of doubt how far the sexual organs are involved in mercury poisoning. According to some authorities disturbances of the menstruation and even complete amenorrhoea have been observed, and abortion is also stated to have been caused by it. A general condition of cachexia may be induced by the presence of these disorders, and is marked by pallor, anaemia, emaciation, weak- ness and restlessness, with a tendency to fainting and disturbed sleep. The pulse is small, weak and quick, sometimes irregular, and the pa- tient often complains of breathlessness. Affections of the central nervous system are rarely induced now by the abuse of mercury in therapeutics, but are mentioned by some of the earlier writers, and still occur in the case of workers in mercury mines, in mirror, barometer and thermometer factories, and in other manufactories in which mercury is used and its fumes are inhaled by the workmen for prolonged periods. One of these affections is the mercurial erethism, a condition of abnormal irritability, timidity or shyness, accompanied by great muscular weakness, and sometimes developing into sleeplessness, delirium and transitory hallucinations. Another well-known form is the mercurial tremor > which affects the hands and arms first, later the legs, and sometimes extends over all the muscles of the body. Shooting pains along the nerves or in the joints are sometimes complained of, circumscribed areas of partial anaesthe- sia, amblyopia, anosmia or deafness have been described, and in some cases localized paralysis of the muscles of the arm or leg has been induced. These last differ from the paralysis of lead or arsenic poi- soning in the fact that no wasting of the muscles is observed, and the electrical reaction remains normal. According to Letulle they are due to the destruction of the myeline sheath of the peripheral nerves, the axis cylinder remaining intact. The symptoms of mercurial poisoning, both acute and chronic, in animals, resemble those in man so closely that it is unnecessary to de- scribe them further. Action Lower Forms of Life. The action of mercury on proteids extends to all forms of living matter. Whenever the metal comes into intimate contact with albumins, it forms the albuminate and destroys life. This poisonous action is naturally much more evident when solu- MERCURY. 639 ble preparations are used than when the oxides or calomel are in ques- tion. Thus corrosive sublimate in a solution of one part in 50,000 destroys infusoria in some 20 minutes, and even one part in one mil- lion kills algse in the course of a few days. The bacteria are some- what more resistant than these forms, but corrosive sublimate is said to delay the development of some of these in a solution of one part in one million, and the anthrax bacillus fails to grow in blood which con- tains one part in 8,000. A solution of one part in one thousand is generally regarded as capable of disinfecting fluids completely in the course of a few hours, but there is no question that the germicidal power of corrosive sublimate has been much overestimated. Thus Geppert found that the spores of anthrax could be exposed to the ac- tion of a one per cent, solution for many hours and still develop as soon as the mercury was entirely removed. There is no doubt, how- ever, that corrosive sublimate and the other soluble salts of mercury are among the most powerful antiseptics at present available. The insoluble preparations are less poisonous, ovying to the difficulty in bringing them into intimate contact with the microbes, but calomel has been shown to have some effect as an intestinal antiseptic. In the Higher Animals and in Man the same destructive effects are induced by the mercury preparations. The corrosion of the mouth, throat and stomach when the perchloride is swallowed, has already been mentioned. When it is applied to the other mucous membranes, Bimilar effects are obtained, and when it is injected hypodermically, even in dilute solution, it induces intense pain, swelling and inflam- mation, which is rarely followed by suppuration, but which may result in the formation of cicatrices. Stronger solutions injected into animals often cause the ' formation of cheesy abscesses, and even dry necrosis of the skin and underlying tissue. The hypodermic or in- tramuscular injection of insoluble preparations is more liable to cause abscess formation, because the mercury is slowly absorbed and has therefore more time to induce its irritant effects. When solutions of corrosive sublimate are applied to the skin, they cause a feeling of numbness very often ; but when very strong solu- tions come in contact with tender parts of the skin, and in particular, when the salt itself is allowed to lie in contact with it for any length of time, deep corrosion, necrosis and sloughing may follow. Even the insoluble preparations are liable to set up irritation when they are rubbed into the skin, especially if there is any pre-existing tendency to cutaneous eruption. After absorption, mercury acts more especially on the alimentary tract and on the kidneys, although other organs are not exempt from its effects. The Salivation and Stomatitis, which are so frequently seen under mercurial medication, are obviously not due to the local action of the drug on its way to the stomach, for they occur equally readily when it is applied by hypodermic injection or by inunction. The salivation is apparently due to the direct action of the mercury on the secretory 640 THE HEAVY METALS. apparatus, for it often appears before any other symptom and is cer- tainly not the reflex effect of the irritation of the mouth. The saliva is sometimes excreted in enormous amounts, many litres of it being poured out in the course of twenty-four hours. It contains mercury, and has therefore a metallic taste, and tends to irritate the lips and skin where it comes in contact with them. In extreme cases it leads to sleeplessness from its accumulating in the back of the throat and awakening the patient with a feeling of suffocation. The stomati- tis is likewise due to the excretion of mercury by the saliva and by the other mucous secretions of the mouth and throat. The irritation caused by the metal leads to excoriations, and these to the formation of ulcers, particularly where microbes are present in large numbers, as around carious teeth. The necrosis of the jaws arises from these ulcers, penetrating to the bone and setting up periostitis, for mercury in itself has no specific action on the bone such as has been mentioned under phosphorus. Mercury has less direct effect on the Stomach, though congestion and even small haemorrhages in cases of poisoning indicate that it is not entirely immune ; the loss of appetite and malnutrition in chronic poisoning are ascribed to the presence of mercury in the saliva rather than to its affecting the gastric functions directly. In the Intestine, on the other hand, mercury is apparently excreted in large amount, and induces very distinct lesions. The parts affected are the caecum and colon, while the small intestine very often escapes almost entirely. The action of mercury is evidenced by hypenemia, redness and swell- ing of the mucous membrane, which later develop into necrotic sur- faces and ulcers along the folds ; these lend it an appearance almost indistinguishable from that of chronic dysentery and may eventually end in perforation. The symptoms from the intestine are in accord- ance with the lesions, consisting in constant purging with very fluid, sometimes rice-water stools, intense pain and tenesmus, blood and frag- ments of mucous membrane in the faeces. Small doses of mercurials given by the mouth act as Purges, causing soft stools generally without pain or straining. The insoluble prepa- rations are used for this purpose, as they act least on the stomach, and the mercurial purges par excellence are calomel and the metallic prep- arations blue pill and gray powder. This effect is apparently due to their acting as intestinal irritants from their specific action on the in- testine. They apparently do not remain long enough in the stomach to be dissolved, and besides seem to have less tendency to induce irri- tation here. In the intestine, on the other hand, their longer sojourn and special affinity for the epithelium, leads to their partial solution and to their irritant action being developed. A small proportion of these insoluble preparations is absorbed from the intestine, but the great mass is thrown out unchanged in the stools, and thus very large doses of calomel sometimes induce no serious symptoms. Mercury acts in the intestine even when the bile is suppressed, and the stools are often of a greenish color, which has been ascribed to a metallic com- MERCURY. 641 pound formed in the bowel, but which is really due to bile pigment. This is ordinarily decomposed by the microbes in the intestine with the formation of the fsecal pigment, but mercury from its antiseptic properties prevents the growth of the microbes, and the bile therefore appears in the stools undecomposed and possessed of its ordinary color. The mercurial purges, and in particular calomel, have often been credited with increasing the secretion of the Bile, but this has been shown to be incorrect, for Stadelmann (in animals) and Pfaff (in man) found that the mercurial preparations had no effect on the secretion escaping from a biliary fistula. The belief probably arose from the green color of the stools, but this, as already mentioned, is due, not to the increase of the bile, but to its being preserved from putrefaction in the intestine. There is, in fact, no sufficient experimental or clini- cal evidence that the liver is in any way affected directly by mercury. The " biliousness " which is so often relieved by calomel or blue pill, is due, not to the liver, but to disorder of the alimentary tract. Mercury has no such powerful effect on the Unorganized ferments of digestion as it has upon the microbes, for though large amounts of the soluble preparations precipitate the pepsin in artificial digestion experi- ments, smaller quantities have little such effect. Calomel has no action on the digestive ferments, but retards the putrefaction in the intestine, and thus limits the decomposition of the food. Its antiseptic action is aided by the increased peristalsis which follows its use, and which removes the decomposing mass from the canal. In fact, the lessened amount of double sulphates in the urine which follows the use of calomel, may be ascribed as much to its purgative, as to its antiseptic power. Another organ which is powerfully affected by mercury is the Kid- ney. A moderate dose of calomel induces marked diuresis, particu- larly in cases in which there is a large accumulation of fluid in the body, as in dropsy from heart disease. In other forms of dropsy, such as that arising from hepatic cirrhosis, or from renal disease, it is less reliable, although it not infrequently increases the flow of urine in these cases also. AYhen purging follows the administration of the mercurial, less diuretic effect is observed. In normal individuals and in animals the diuretic action is gener- ally much weaker, although some recent work has shown that it can be elicited easily in rabbits (Cohnstein). In view of the fact that mercurial preparations have an irritant action on the kidney, it would seem that the increased secretion of urine induced by calomel and by other mercurials is most probably to be ascribed to a direct action on the epithelium. In acute mercurial poisoning, when death does not follow in the course of a few hours, anuria is often observed both in man and animals. This anuria is due to the renal changes, which are found to consist in necrosis of the epithelium of the tubules in some parts of the cortex. 41 642 THE HEAVY METALS. The whole organ is congested and the glomeruli are in a state of acute inflammation, but the necrosed tubules are the most prominent feature. Very generally in the rabbit, less often in the dog and in man, these are filled with a deposit of phosphate of calcium, occasionally in- termixed with some chalk. According to some pathologists, it is deposited first in the tubules and only when these are filled does it force its way into the cells, but a more probable view is that it is thrown out in the necrosed cells, and as these break up, passes into the tubules. It may be remarked in passing that several other poisons, such as bis- muth and aloin, occasionally induce this deposit of lime in the kidneys. These renal symptoms have been observed most frequently in cor- rosive sublimate poisoning, either by the mouth, or from absorption from a wound. The more slowly absorbed, insoluble preparations ap- parently do not often accumulate in sufficient quantity in the blood to induce such severe effects. At the same time, albumin or casts are very often observed in the urine from the treatment of syphilitic pa- tients with mercury in any form, although it is stated that this is less liable to occur when soluble preparations are injected hypodermically than after inunction or the use of insoluble salts subcutaneously. The more marked the action on the intestine, the less destruction of the kidney is observed in cases of severe poisoning. The lime deposited in the kidney has suggested the idea that mercury has a specific action on Bone, consisting in the absorption of the calcium, and an attempt has been made to demonstrate this action by estimating the lime salts in bone after mercury, and comparing the amount with that of normal animals of the same size. No action on bone has been established, however, and the explanation of the renal deposit as due to decalcification of the bones has been shown to be incorrect by Klemperer, who found that, instead of being oversaturated with lime which it deposits in the kidney, the blood actually con- tains a somewhat smaller amount of lime than normally. The lime deposited in the kidney is evidentally drawn from that normally circulating in the blood ; in necrosed tissue from other causes lime is very often deposited, although not so rapidly as in mercury poisoning. Large doses given repeatedly lead to an increase in the size and number of the vessels of the bone-marrow and the fat cells atrophy rapidly ; later, gelatinous degeneration follows and the cellular ele- ments of the marrow disappear. Mercury seems to have comparatively little direct action on the Circulation in cases of poisoning, and most of the changes in the pulse are to be ascribed rather to the shock and collapse, or in chronic poisoning to the cachexia and malnutrition, than to any direct effects on the heart and vessels ; in some cases of acute poisoning, however, patches of fatty degeneration have been found in the heart. In the frog large doses of soluble salts slow and weaken the heart, and mercury salts injected into the blood vessels of mammals have been found to cause a sudden descent of the blood-pressure and paralysis of the heart. Sub- cutaneously injected into animals, the soluble salts reduce the blood-pressure more gradually, but at the end a very sudden descent to zero occurs. The action is in part on the heart muscle, in part on the peripheral vessels. The Respiration is also only affected indirectly. In chronic mercury poi- soning, marked breathlessness is sometimes observed and has been ascribed by Kussmaul to the general muscular weakness. MERCURY. 643 The action of mercury on the Nervous System is very obscure. In acute poisoning the intellect often remains clear to the end, and no symptoms pointing to any direct affection of the central nervous system are observed. In chronic poisoning, however, the higher cen- tres are undoubtedly involved in the effects, as is shown by the erethism and occasional hallucinations. The tremor is also of cerebral origin probably, though this is not yet certain, and the general muscular weakness is not due to the peripheral muscles and nerves being affected, but to the alterations in the centres. As regards the paralysis sometimes observed in the arms or legs in workers in mercury, Letulle believes it to be caused by the poison acting on the peripheral nerves and destroying the myeline sheath. The areas of partial anaesthesia and the pains in joints may also prove to be due to peripheral changes. In some cases, especially where the tremor is marked, the reflex excitability of the spinal cord has been found to be exaggerated, but it is generally unaf- fected. The muscles do not seem to be acted on directly in either acute or chronic poisoning in man, and even when paralysis is de- veloped, they maintain their irritability and do not atrophy. In the frog mercury weakens the muscles, but only after doses which are suf- ficient to paralyze both the central nervous system and the heart. A good deal of interest has been manifested in the question whether mercury affects the Nutrition in any way except through its action on the alimentary canal. Several authors have stated that the urea is in- creased by the use of small doses, but the subject is a very difficult one to investigate, for when any save the smallest doses are given, the kidney and bowel are involved in the effects, and the prolonged use of mercury is restricted to experiments on animals and on syphilitics. There seems, however, good reason to believe that very small doses of mercury given for some time increase the nutrition and weight of ani- mals. The cachexia of chronic poisoning may be due in part to a specific action on the metabolism, but it is impossible to determine this point, because the alterations in the alimentary tract are in them- selves sufficient to cause such symptoms. Meyer found that mercury lessened to some extent the alkalinity of the blood, probably by the formation of lactic acid in excess. Changes in the Blood Corpuscles have been observed under mercurial treatment in a number of instances, but there is as yet no general agreement as to wherein these consist, and it seems not unlikely that the blood reaction in health is different from that in syphilis and that it may vary in the successive stages of the disease. In health the red corpuscles and the haemoglobin are said to be augmented at first but afterwards diminished, while in syphilis a sharp fall in the amount of haemoglobin is succeeded by an increase to beyond that present before the treatment. Kuperwasser states that in healthy persons mercury increases the number of newly formed leucocytes but that this is more than counterbalanced by the fall in the older cells ; in syphilis he found fewer recently formed leucocytes and more mature ones after mercury. 644 THE HEAVY METALS. Mercury has no effect on the Temperature in itself, but when sto- matitis or skin eruptions are developed, some fever generally accom- panies them, while in collapse the temperature may fall several degrees below the normal. Distribution. After its prolonged use mercury is found in almost every organ of the body, but larger quantities are found in the kidney and liver than elsewhere, and it seems to be stored in these organs longer than in any other. In cases of acute poisoning through ab- sorption from the subcutaneous tissue or from wounded surfaces, the distribution is the same. The statement that mercury is stored up in large quantities in the bones has not been confirmed by the more re- cent investigators, but traces are found here, as in the muscles, brain, lungs, intestine and spleen. Mercury is Eliminated by almost all the excretory organs, but most largely by the intestine and kidney. It has been found in small quan- tities in the perspiration, milk, saliva, gastric juice and bile, and has been shown to pass to the foetus in utero through the placental circu- lation. The excretion begins within one or two days after absorption, but is very slow and irregular. Mercury has certainly been found in the urine six months after its administration had been stopped, and some authors state that it may be detected in it for years afterwards. It is open to question, however, whether these last cases of very pro- longed excretion are not to be explained by the patients having been exposed to the fumes of mercury in the interim. At the same time it is not impossible that pockets of mercury may be encapsuled in the tissues when the insoluble preparations are injected, exactly as a lead bullet may be, and that after a long time some irritation such as a blow may again liberate it and permit of its excretion. The elimination is said to last longer when the mercury is rubbed into the skin than when it is given by the mouth, or when soluble preparations are in- jected hypodermically. This is explained by the drug passing more slowly through the skin, which continues to contain some of it long after the inunction treatment has ceased. Mercury often disappears from the urine for several days or even weeks at a time, and then re- turns again. It is said that more mercury is found in the urine after its hypodermic injection than after inunction, but even in the most favorable circumstances only a small proportion of that absorbed is excreted by the kidneys. In the urine the mercury probably exists for the most part in the form of a salt, although some of it may be in organic combination. Mercury forms very poisonous compounds with methyl and ethyl, which are apparently very slowly decomposed in the organism to ordinary forms, and which have given rise to fatal poisoning in two cases, the symptoms making their appearance only long after the ingestion. 1 Therapeutic Uses. The chief purpose for which mercury is used in- ternally is the treatment of Syphilis. Its curative effects in this dis- 1 Hepp, Arch. f. exp. Path. u. Phann., xxiii., p. 91. MERCURY. 645 ease can be explained at present only by supposing that it develops a specific destructive action on the syphilitic virus. Its virtues are attested by the great majority of the medical profession, but a com- paratively small minority still oppose its use, and some have even gone so far as to assert that instead of curing syphilis it promotes the development of tertiary symptoms. Less extreme opponents of the mercurial treatment hold that, while the secondary symptoms cer- tainly disappear under it, they are only rendered latent, and reappear in course of time, whereas without mercury they would have run their course in the first instance and disappeared. There is no ques- tion that a certain proportion of cases of syphilis recover without the use of mercury, and indeed without the use of any drug. In many of these, however, the course of the disease can be shortened by mer- cury, and in many others, in which the symptoms show no signs of abating under hygienic measures, mercury causes a rapid and perma- nent improvement. A certain number of relapses undoubtedly occur after the mercurial treatment has been left off, but it seems probable that many of these would not have had even temporary relief without mercury. As to the old argument that tertiary syphilis is caused by the use of mercury in the earlier stages, it has been shown that tertiary syphilis occurs without mercury, and that the lesions caused in it are entirely different from those induced by this metal. The opponents of mercurial treatment frequently assume that it is necessarily followed by cachexia and by all the lasting disorders which its abuse leads to. At the present time, however, mercury is administered in small quan~ tities, and syphilologists are agreed that it ought not to be allowed to induce any but the earliest symptoms of chronic poisoning. To sum- marize the view held by the great majority of authorities, it may be said that mercury is of benefit in a very large proportion of cases, although it is not essential to the treatment of some favorable ones, and that it is unable to arrest the progress of the disease in a certain proportion of malignant forms. A question that is still debated, and which, like the other matters of doubt concerning the mercurial treatment of syphilis, has given rise to an overwhelming literature, is whether mercury ought to be exhibited as soon as the diagnosis of primary syphilis is made, or whether the advent of the secondary stage is to be awaited. Practice differs in this respect, but probably the majority of physicians do not prescribe mer- cury until some secondary symptom makes its appearance, and then continue its administration until the disease disappears, or until sali- vation or stomatitis warns against its further use. Some authorities recommend that mercury be continued for months after the secondary symptoms have been relieved, in order to prevent relapse, but this is less rigidly carried out now than in the earlier decades of last century, In tertiary syphilis mercury is generally considered inferior to the iodides, but when the disease attacks any important organ, such as the brain or eye, mercury is more reliable, or both mercury and iodide may 646 THE HEA VY METALS. be prescribed together. In hereditary syphilis mercury is much more efficient than iodides. Mercury has been used in syphilis in a large number of forms, and of late years new preparations and new methods of administration have succeeded each other so rapidly that it is impossible to discuss them all. Formerly mercury was given by the mouth or by inunction, and apart from the special clinics and the syphilologists, the internal treatment is still the most popular one. The preparations generally used for internal administration are corrosive sublimate, calomel, or the metallic preparations blue pill and gray powder the last being used most widely in England. Calomel and the metallic preparations are, however, very liable to induce diarrhoea, from their being insoluble and thus passing into the intestine before being absorbed, and opium is therefore often prescribed along with them. Calomel is also credited with causing salivation and stomatitis more readily than the other preparations, perhaps because it is more difficult to gauge how much of it is absorbed than in the case of the soluble perchloride. Mercury administered by the mouth is in all cases more liable to derange the digestion than when administered by other channels. Accordingly, inunction was introduced to avoid the disturbance of the stomach and intestine caused by the local action of the mercury, while that due to its excretion along the alimentary tract remained unchanged. By this method the mercury is rubbed into the skin in the form of ointment ; that most frequently used consists of metallic mercury suspended in a state of fine division in lard, but others have been suggested, such as the oleate of mercury, the ointment of the yellow oxide, and mercury soaps. The first is less irritant, however, and has entirely supplanted the others, which never enjoyed a very wide popularity. The action of mercury is somewhat more slowly elicited by this method than when it is administered internally, but lasts longer, and the digestion is less liable to be disturbed. The mercury is absorbed in the form of a proteid combination from the gland ducts, and probably a small quan- tity is inhaled by the lungs as vapor. The objection to the method is that it is inconvenient and uncleanly, and that it is even less possible to estimate the amount of mercury actually absorbed than when it is given by the mouth. One case of fatal poisoning has been recorded from the ointment being applied to sore hands. Instead of mercury ointment being rubbed into the skin, one of the plasters or lint con- taining mercurial ointment (Weylander) may be applied to it, permit- ting of the continuous absorption of small quantities by the skin and by inhalation of the vapor. In 1867, Lewin introduced the hypodermic or intramuscular injection of a dilute solution of corrosive sublimate, and this has been very widely practised of late years, and with great success. The advantages of the method are the avoidance of digestive disturbance, which is shared by the inunction method, its cleanliness, the more accurate esti- mation of the amount of mercury actually administered, and the greater MERCURY. 647 rapidity of action. Its chief disadvantage is the pain caused by the injection, which has to be repeated daily ; some inflammation and swelling follow immediately, but no suppuration, when ordinary care is taken ; but the pain is very intense and persistent and many patients refuse to continue the treatment. Salivation is said to follow this method more seldom than any other, and relief from the secondary syphilitic symptoms is gained sooner. Lewin continues to use the per- chlpride solution and prefers it to any of the modifications ; others have added morphine, or, more recently, cocaine, in order to lessen the pain, but this is to be deprecated from the danger of the habit being formed. The addition of chloride of sodium tends to prevent the pre- cipitation of proteids by the perchloride, and a solution of perchloride of mercury, with ten times its weight of common salt or of urea has therefore been advocated, while others have used the peptonate or the albuminate of mercury dissolved in salt solution. Mercury has a strong affinity for the amido-group, and in combination with it has little ten- dency to precipitate proteids, and this has led to the use of preparations of mercury with the amido-acids, such as glycocoll, formamide or suc- cinimide. Many of these methods are said to lessen the pain of hypo- dermic injection, but do not remove it entirely, probably because the various compounds undergo some dissociation in the tissues, and the free mercury ion causes the same irritation as if the perchloride had been injected. Instead of the soluble preparations of mercury, which necessitate the painful injections being repeated daily, insoluble salts have been injected, with the idea that these being slowly dissolved and absorbed from the seat of injection, a quantity sufficient for several days may thus be given at one time. Instead of injecting these insoluble prep- arations hypodermieally, they are often thrown into the muscular tissue. According to the advocates of this method, it causes less immediate pain than perchloride injections, but, as solution takes place, and the mer- cury attacks the tissues, the part becomes extremely painful, swollen, and inflamed. Suppuration and even gangrene have been developed in a very considerable number of cases, and in others severe or fatal mercury poisoning has been observed. The advantages of the method are that the physician has not to visit the patient every day, and that the injection need only be made once, or at most twice a week. On the other hand, the local lesions are often very severe, and the amount of mercury absorbed cannot be controlled in any way. It has the ad- vantage over the administration per os that the digestion is not so liable to be interfered with, but, as has been said, the danger and pain are very much greater. Many authorities therefore deprecate the use of these insoluble preparations by injection, but a considerable number of syphilologists still persist in their use, and new preparations have been introduced for this purpose in large numbers. Those most commonly used are calomel in salt solution or in liquid paraffin, me- tallic mercury in very fine division suspended in liquid paraffin, the 648 THE HEA VY METALS. salicylate, benzoate, and the thymol-acetate. The oxides have also been proposed and many other preparations have received a trial by this method. Other methods of introducing mercury into the tissues are more rarely employed. The intravenous injection of the perchloride has been suggested for the treatment of cases in which there is urgent haste, but has rarely been carried out, and is likely to prove dangerous from the formation of emboli, and also from the effects of mercury on the heart when thus applied. Suppositories of mercury have been used to some extent, and are said to disturb the digestion less than the administration per os. Mercury fumigations have also been practised to a limited extent, the vapor of mercury being freed by heating calomel or the sulphide. The pa- tient sits in a wooden tent up to his neck and the mercury deposited on the skin is absorbed. The method is very cumbrous, and the quantity of mer- cury taken up cannot be controlled. Mercury was recommended by Hamilton in the beginning of last century in the treatment of Acute Febrile Affections, and the greatest abuse unquestionably prevailed in the earlier decades. Later its sphere of usefulness was restricted to the treatment of inflammation of the serous membranes pleurisy, meningitis, pericarditis, peritonitis and many physicians still maintain that it checks the effusion and pro- motes the healing of these diseases. Others deny that mercury pos- sesses any virtues in these cases, and its use is undoubtedly becoming more limited ; in acute iritis it is still used almost universally. In these cases it is always administered by the mouth in the form of calomel, blue pill or gray powder. As a Purgative mercury is very frequently prescribed in " bilious- ness," and in putrefactive diarrhoea. It acts partly from its antiseptic power, but mainly by removing the putrefying contents from the in- testine ; calomel, blue pill, or gray powder is usually employed with or without the addition of a vegetable purge. Calomel has proved of only doubtful value as an intestinal antisep- tic in typhoid fever, dysentery and other similar conditions. Calomel and other mercurials have long been known to be of value in cases of Dropsy, but Jendrassik deserves the credit of having re- vived their employment as diuretics, for this use of mercury had fallen into oblivion. The best preparation is calomel, given in 0.2 G. (3 grs.) doses three times a day or in 0.1 G. (2 grs.) doses 5-10 times a day. It is of great value in certain cases of cardiac dropsy, but is less reliable in the accumulations of fluid met with in hepatic or renal disease, although here too its administration is sometimes followed by the rapid excretion of the fluid. It does not seem to be contraindi- cated in chronic nephritis, although its action has to be carefully con- trolled. It has no effect in removing the exudations of acute inflam- mation such as pleurisy. Mercury is used Externally as an Antiseptic wash in surgical opera- tions, chiefly in the form of the perchloride, but also as the cyanide MERCURY. 649 and oxycyanide. It is irritant to wounds, however, and is liable to be absorbed when applied to large surfaces, and several cases of fatal poisoning have been recorded from the use of even the most dilute solutions of corrosive sublimate to wash out the uterus and vagina. These preparations, more especially the perchloride, have also the dis- advantage of attacking steel instruments. Numerous ointments have been applied externally in the treatment of Skin Diseases, particularly those of a parasitic nature, such as itch, and in condylomata, ulcers and skin diseases of syphilitic origin. These preparations combine an antiseptic with a more or less irritant action, and unlike carbolic acid and its allies, are equally powerful antiseptics in ointments and in water. The least irritant of the phar- macopoaial ointments is the mercury ointment ; then the oleate, yel- low oxide, red oxide, and ammoniated mercury follow in order, while citrine ointment is much more irritant and corrosive. Other external applications are the plasters and the black and yellow wash. Oint- ments containing calomel, corrosive sublimate, and other preparations are sometimes prescribed, or calomel may be used as a dusting powder in syphilitic ulcers. The mercury ointments are frequently applied to the eye, the milder ones as antiseptics and slight irritants, citrine oint- ment to destroy granulations. Mercurial ointments are sometimes employed to promote the absorp- tion of subcutaneous effusions and to reduce swellings. They are not superior to other irritants for this purpose, however, and have the dis- advantage of permitting the absorption of a dangerous poison. The nitrate of mercury and its ointment (citrine) are sometimes used as caustics for application to the os uteri, condylomata and elsewhere. Mercury treatment is Contraindicated, or requires special caution in cases of profound cachexia, weakness, or anaemia, unless these arise from syphilis. Where the digestion is weak, it ought to be avoided if possible, and in cases of tuberculosis there is always the danger that the disturbance of the digestion may accelerate the course of the dis- ease. In severe nephritis it is also to be used with caution, although it is beneficial in some cases, and although some authorities deny that it is injurious even when it has no diuretic action. In pregnancy mer- cury is not absolutely contraindicated, at any rate up to the sixth month. Later it is liable to injure the patient by its action on the di- gestion, and in some cases has induced abortion ; the child may also suffer from mercurial poisoning. Mercurial ointments or dusting powders have to be used with care when iodides are being administered internally, as the iodide excreted forms the iodide of mercury, and this may cause violent corrosion. Thus in the eye, severe effects have been induced by the application of calomel to the cornea while iodide was being given. In cases of Acute Corrosive Poisoning, the indications are the evac- uation of the stomach, preferably by the stomach tube. Tannic acid, or eggs, milk and other albuminous substances may be given to pre- 650 THE HEAVY METALS. cipitate the metal and protect the mucous membrane. The treatment of the later symptoms is the same as that of the chronic form. In Chronic Poisoning the salivation and stomatitis are treated by the use of chlorate of potash solution as a mouth wash, and its free applica- tion during mercurial 'treatment, along with careful brushing of the teeth, is believed by most physicians to hinder the onset of the symptoms. Tannic acid solution is also recommended as a mouth wash. The diarrhoea may be treated with opium, the other symptoms on general principles. In any case the drug ought to be abandoned, or the dose much reduced as soon as the salivation becomes marked. In chronic poisoning not arising from the therapeutic use of the drug, iodide of potassium is generally prescribed, although its utility has not yet been placed beyond question. Sulphur baths, and hot baths without sulphur are also recommended. PREPARATIONS. HYDRARGYRI CHLORIDUM CORROSIVUM (U. S. P.), HYDRARGYRI PER- CHLORIDUM (B. P.), CORROSIVE SUBLIMATE (HgCl 2 ), forms heavy, colorless crystals, without odor, but possessing an acrid, metallic taste, soluble in 16 parts of cold water, in 2 parts of boiling water, in 3 parts of alcohol, and in 4 parts of ether. LIQUOR HYDRARGYRI PERCHLORIDI (B. P.) contains ^ gr. in a fluid dr., -1 fl. dr. Corrosive sublimate is one of the most irritant preparations, and is rapidly absorbed. It is used internally in syphilis, 0.002-0.02 G. (yV-i g r O/ in one per cent, solution and is also injected hypodermically in 0.6 per cent, solu- tion, 2 c.c. (30 mins.) daily. This solution is often made up with 6 per cent, of sodium chloride or urea. Perchloride of mercury is less liable to induce salivation, but disturbs the digestion more than other preparations when given internally, while its hypodermic injection is exceedingly painful. It has induced fatal poisoning in the dose of 0.18 G. (3 grs.), taken by the mouth, but in other cases much larger quantities have been recovered from. It is stated that opium eaters can take enormous quantities without evil effects. It is used extensively in surgery as an antiseptic solution (1 in 2,000-4,000), to disinfect the hands, wounds, etc., but is irritant to delicate tissues, such as the peritoneum, and corrodes steel instruments. It is also used in the form of a soap and to impregnate bandages, cotton-wool, gauze, catgut and silk. It preserves its antiseptic action in oils and ointments. It has been used to a limited extent in skin diseases in solution, in baths, or in ointment, as a local application in diphtheria, and as an intestinal antiseptic in putrefactive diarrhrea, typhoid fever and cholera. The albuminate and peptonate of mercury are formed by precipitating a solution of egg albumin or of meat peptone with a five per cent, solution of corrosive sublimate. The precipitate is collected, washed and dissolved in 20 per cent, chloride of sodium solution. It was hoped that these prepara- tions would not cause irritation and pain when injected subcutaneously, but this anticipation has not been fulfilled and they have fallen into almost complete disuse. They are not official. Hydrargyri Cyanidum, mercuric cyanide (Hg(CN) 2 ), colorless crystals, without odor but with a bitter, metallic taste, soluble in about 12 parts of water, in 15 parts of alcohol. The cyanide resembles the perchloride in its action and has been used hypodermically in syphilis. As a surgical antiseptic it is equal to 1 The B. P. gives as the dose or corrosive sublimate and the red iodide, g^-ie r - MERCURY. 651 corrosive sublimate and attacks steel instruments less. Dose, as of corrosive sublimate. The oxy cyanide of mercury. (Hg 2 O(CN) 2 ) is also used to form an antiseptic lotion in surgery. The double cyanide of mercury and zinc has been recom- mended by Lister for this purpose. HYDRARGYRI IODIDUM KUBBUM (U. S. P., B. P.), red iodide.of mercury, biniodide of mercury (HgI 2 ), a scarlet-red, amorphous powder, tasteless and odorless, almost insoluble in water, but soluble in solution of iodide of po- tassium. 0.005-0.02 G. GV-i gr.), (B. P.sVrV gr-)- This preparation is very seldom prescribed as such, but is frequently formed by prescribing a mixture of corrosive sublimate and potassic iodide, when the iodide of mercury is formed and is kept in solution by the excess of the iodide of potassium. This prescription is often indicated in the transi- tional period between secondary and tertiary syphilis, and even when the tertiary symptoms are fully developed. Liquor Arseni et Hydrargyri lodidi (U. S. P., B. P.), Donovan's solution, contains one per cent, each of arsenic iodide and red mercuric iodide. Used as a tonic in syphilitic and other cases. 0.3-1.3 c.c. (5-20 mins.). Unguentum Hydrargyri lodidi Rubri (B. P.), 4 per cent. HYDRARGYRI CHLORIDUM MITE (U. S. P.), HYDRARGYRI SUBCHLORIDUM (B. P.), mild inercurous chloride, CALOMEL (Hg 2 Cl 2 ), a heavy white powder without odor or taste, insoluble in water, alcohol and ether. 0.03-0.3 G. (-5 grs.) in powder, less suitably in pill form. Pilulse Antimonii Composita (U. S. P.), Pilula Hydrargyri Subchloridi Com' posita (B. P.). See Antimony, page 633. Unguentum Hydrargyri Subchloridi (B. P.), 10 per cent. Calomel is contained in the compound cathartic pill U. S. P. (p. 105). Calomel is used in syphilis (dose, 0.05 G. (1 gr.) thrice daily), but is credited with being more liable to induce salivation than other preparations, and its purgative action often has to be counteracted by opium. A suspension of 1 part calomel in 20 parts of 10 per cent, salt solution or of liquid paraffin is often injected into the buttock in syphilis ; the dose of calomel by this method is 0.05-0.1 G. (1-1? grs.) once a week. As a purge and intestinal disinfectant it is of value in biliousness, and in the diarrhrea of putrefaction, less so in diseases in which the intestinal wall is the site of infection, as in typhoid fever and cholera. Calomel causes less irritation and colic than most other purges, and small doses are followed by only one evacuation. It may therefore be given where pre- existing irritation of the intestine contraindicates the use of most other pur- gatives. Calomel is often advised in hepatic affections, but it is a question whether it has any effect here except as a purge. It is of great value in some forms of dropsy, especially those of cardiac origin, in which it is administered in 0.2 G. (3 gr.) doses thrice a day for 2-4 days, and is stopped as soon as the diuresis sets in. The treatment may be repeated if the dropsy returns. Alkalies are often added to calomel prescriptions on the ground that in this way there is less danger of the calomel being changed to corrosive sublimate in the stomach. For the same reason, acids are often avoided for some time after calomel is taken. As a matter of fact these fears are quite groundless, as calomel is not changed to the perchloride in the stomach and it is there- fore quite unnecessary to add alkalies to calomel. Calomel has been used externally as a dusting powder for syphilitic condylomata, as a slight irritant to the cornea and as an ointment in pruritus and other skin diseases. Hydrargyri lodidum Flavum (U. &. P.), yellow or green iodide of mercury (Hg 2 I 2 ), a bright yellow amorphous powder, tasteless and odorless, insoluble in water, alcohol or ether. It has been used in syphilis, with the idea of uniting the virtues of the iodides and of mercury. But the quantity of iodide is altogether inadequate 0.05-0.2 G. (1-3 grs.). 652 THE HEAVY METALS. HYDRARGYRUM CUM GRETA (U. S. P., B. P.), mercury with chalk, GRAY POWDER, is formed by rubbing up metallic mercury with chalk and honey (U. S. P.) until the mercury is divided into very fine globules, each encased in chalk. It forms a light-gray, somewhat damp powder, without odor and with a sweetish taste from the honey. The mercury (38 per cent. U. S. P. , 33 per cent. B. P.), remains in the metallic state, very little oxide being formed. It is insoluble in water, alcohol and ether, and is always prescribed in powder form. 0.1-0.5 G. (2-8 grs.). MASSA HYDRARGYRI (U. S. P.), mass of mercury, BLUE MASS, BLUE PILL, is formed from metallic mercury by rubbing it with Mel Rosse, glycerin, al- thaea and liquorice until the globules are invisible under a lens magnifying ten diameters. The blue mass contains about 33 per cent, of mercury almost entirely in the metallic form. It is of the consistency of pills and is always prescribed in this form. 0.2-0.5 G. (3-8 grs.). PILULA HYDRARGYRI, BLUE PILL, the corresponding B. P. preparation, is made up with confection of roses and liquorice by rubbing them with metallic mercury until the glolbules are no longer visible. 4-8 grs. These preparations are very largely used as mild mercurial purgatives, the blue pill being frequently reinforced by the addition of one of the vege- table purges. The gray powder is especially adapted for children, and is of value in summer diarrhoea and other similar conditions. Blue pill is often given in cardiac dropsy along with squills or digitalis, but has proved inferior to calomel as a diuretic. Gray powder is held by some authorities to be the best form for the internal treatment of syphilis, and is given in doses of 0.05 G. (1 gr.) 3 to 5 times a day ; if necessary, opium may be given to prevent purging. The blue pill may also be used in syphilis and is less liable to purge. UNGUENTUM HYDRARGYRI (U. S. P., B. P.), mercurial ointment, BLUE OINTMENT, is formed by triturating metallic mercury with lard and suet and oleate of mercury until the globules are invisible when magnified ten diam- eters. The ointment contains about one half its weight of metallic mercury along with a small proportion of oleate. Unguentum Hydrargyri Compositum (B. P.) contains camphor and is some- what weaker than blue ointment. Unguentum Hydrargyri Dilutum (U. S. P.) contains 2 parts of mercurial ointment with 1 part of petrolate. The famous blue ointment is used largely in many forms of skin diseases, especially in those of syphilitic origin, and was formerly the ordinary treat- ment for scabies, in which, however, it has been supplanted by balsam of Peru and other remedies, though it is still used occasionally to destroy pediculi. The most important purpose for which blue ointment is applied at the pres- ent time is the treatment of syphilis by inunction. For this purpose 2-4 G. (-1 dr.) is rubbed in daily in different parts of the body, in order to avoid the irritation induced by applying it repeatedly to one spot. A warm bath is taken first, and the patient then rubs in the ointment on the inside of the thighs, next day on the inside of the arms, on the following days on the forearms, legs, abdomen and back, returning to the thighs on the seventh day and repeating the series. The treatment is continued for a fortnight or three weeks. This method has the advantage that the digestion is less af- fected than when the drug is given internally, but on the other hand, the mer- cury is more slowly absorbed than by other methods ; and no estimate of the quantity really taken up can be formed, as, although the patient is directed to rub it in until the whole disappears, the instructions may be imperfectly carried out. Salivation is not so readily* produced as by the administration per os, but when it occurs, it lasts longer and may become severe. One case of fatal poisoning has been recorded from the application of the ointment, but in this case the skin appears to have been broken. Skin rashes are more fre- quent from inunction than from any other method of application, and finally, MERCURY. 653 the method is extremely inconvenient and dirty. The patient ought to carry out the inunction himself, for any other person doing so may acquire chronic poisoning from absorption through the hands, and eveu if this is prevented by the use of gloves of India-rubber or oiled bladder, some mercury may be absorbed by the lungs. In children the ointment is often applied by spread- ing it on a bandage, which is then applied around the waist. In skin disease and in very hirsute individuals, the inunction treatment is impossible. Oleum Cinereum, or gray oil (not official), is a suspension of metallic mercury in liquid paraffin or in lanolin and oil, and is used in syphilis by intramuscular injection. It often is made up to contain 20 per cent, of mercury, and the dose is then 2-3 c.c. once a week. Olealum Hydrargyri (U. S. P.), Hydrargyri Oleas (B. P.), oleate of mercury, has been used for the same purposes as mercury ointment, but is somewhat more irritant and possesses no compensating virtues. Unguentum Hydrargyri Oleatis (B. P.), 1 part in 4. Emplastrum Hydrargyri (U. S. P., B. P.), mercury plaster, is formed in the same way as the ointment by the trituration of metallic mercury. Emplastrum Ammoniaci cum Hydrargyro (B. P.) is similarly formed, but con- tains less mercury and a large quantity of a gum- resin (ammoniac). These plasters are sometimes applied to chancres and to syphilitic ulcers, and mercury plaster has been applied instead of the ointment as a treatment of syphilis. Linimentum Hydrargyri (B. P.). HYDRARGYRI OXIDUM FLAVUM (U. S. P., B. P.), yellow mercuric oxide. HYDRARGYRI OXIDUM EUBRUM (U. S. P., B. P.), red mercuric oxide. UNGUENTUM HYDRARGYRI OXIDI FLAVI (U. S. P. 10 per cent., B. P. 2 per cent.). UNGUENTUM HYDRARGYRI OXIDI EUBRI (U. S. P., B. P.), 10 per cent. The two oxides are identical in constitution (HgO), but the yellow is obtained by precipitation from the perchloride, the red by oxidation of the metal by means of nitric acid. The red is crystalline, the yellow amorphous, and both are practically insoluble in water and alcohol, but are soluble in acids. The red oxide is more irritant than the yellow on account of its crystalline form, and perhaps also because it often contains some nitrate. The yellow oxide is used in ointment in various diseases of the eye, and both are employed as applications to syphilitic sores, condylomata, and chancres, although the red is often preferred for this purpose. They have also been proposed for hypodermic injection suspended in water. Two famous preparations of mercury are the black and the yellow wash, the former prepared from calomel, the latter from corrosive sublimate by the action of lime water. The black wash, Lotio Hydrargyri Nigra (B. P.), con- tains mercurous oxide (Hg 2 O), the yellow, Lotio Hydrargyri Flava (B. P.), mercuric oxide (HgO). The oxides are in both cases insoluble and the lotions have to be shaken before application. They are used in syphilitic lesions as local remedies. Hydrargyrum Ammoniatum (U. S. P., B. P.), mercuric ammonium chloride, white precipitate (XH 2 HgCl), is formed by precipitating corrosive sublimate with ammonia, and is a white, amorphous powder, without odor and with an earthy, metallic taste, almost insoluble in water and alcohol. Unguentum Hydrargyri Ammoniati (U. S. P., B. P.), 10 per cent. The white precipitate is not used internally, and is more irritant than the oxides. The ointment is occasionally applied in skin diseases and to destroy parasites. Liquor Hydrargyri Nitratis (U. S. P., B. P.), solution of mercuric nitrate, contains about 60 per cent, of the nitrate (Hg(NO 3 ) 2 ) along with about 11 per cent, of free nitric acid. It is a powerfully corrosive fluid which is used to cauterize the os uteri, cancers or condylomata. Symptoms of mercury poisoning have arisen from its application to the os uteri. 654 THE HEAVY METALS. UNGUENTUM HYDRARGYRI NITRATIS (U. S. P., B. P.), citrine ointment, is used, diluted with oil or lard, in conjunctivitis, and also as an application to syphilitic sores and gangrenous ulcers. Unguentum Hydrargyri Citratis Dilutum (B. P.). Hydrargyrum (U. S. P., B. P.), metallic mercury, is not used in thera- peutics at the present time. It was formerly employed in cases of intestinal obstruction in large quantities (up to a pound or more) in order to drag the intestines into place by its weight. As a general rule no symptoms of poison- ing occurred, the mercury being voided unchanged and unabsorbed, but in some cases salivation followed its use. A large number of new preparations of mercury have been introduced of late years and have received a more or less extensive trial, but have seldom been found to be superior to the older forms. Among these may be mentioned the tannate, which was introduced in the hope that it would cause less pur- gation than calomel, and might therefore be better adapted for the treatment of syphilis. 0.1-0.3 G. (2-5 grs.) in powder. The carbolate, salicylate (either neutral or basic), benzoate, sozoiodolate, thymol-acetate and many other similar compounds have been used instead of calomel for hypodermic or intramus- cular injection, have each in succession been blazoned forth as the best preparation, and will probably be forgotten in the course of a few years. Several amido acid salts of mercury such as the formamide, the amido-pro- pionate (alanin mercury) and the succinimide have been proposed as substi- tutes for corrosive sublimate in hypodermic injection. It was believed that the affinity of mercury for nitrogen being satisfied in these compounds, it would attack the proteids less, and as a matter of fact, the injections are said to be less painful than those of corrosive sublimate. Dreser has recently proposed mercuric-potassic hyposulphite, because the mercury is apparently contained in it in a form which does not admit of its dissociation. Colloid mercury has been suggested for inunction instead of the blue ointment. BIBLIOGRAPHY. Chittenden. Johns Hopkins Hosp. Bull. 98, 1899. Saikowsky. Virchow's Arch., xxxvii., p. 346. Rosenbach. Ztschr. f. ration. Med., xxxiii., p. 36. Radziejewski. Arch. f. Anat. u. Phys., 1870, p. 55. Heilborn. Arch. f. exp. Path. u. Pharm., viii., p. 361. V. Mering. Ibid., xiii., p. 86. Meyer. Ibid., xvii., p. 304. Grawitz. Deutsch. med. Woch., 1888, p. 41. Keyes. Am. Journ. of Med. Scien., 1876, p. 17. Schtesinger. Arch. f. exp. Path. u. Pharm., xiii., p. 317. Wilbouchewitch. Arch, de Physiol., 1874, p. 509. Letutte. Arch, de Phys., 1887, i., p. 301. Rosenthal. Berl. klin. Woch., 1895, p. 500. Morel-Lavalle. Kev. de Med., 1891, p. 449. Jendrassik. Deutsch. Arch. f. klin. Med., xxxviii., p. 499; xlvii., p. 22& Bieganski. Ibid., xliii., p. 177. Stintzing. Ibid., xliii., p. 206. Sklodowski. Ibid., Hi., p. 300. Rosenheim. Zts. f. klin. Med., xiv,, p. 170. Cohnstein. Arch. f. exp. Path. u. Pharm., xxx., p. 132. Justus. Virchow's Arch., cxl., p. 91 ; cxlviii., p. 533. Kaufmann. Ibid., cxv., p. 71, and cxvii., p. 227. Xlemperer. Ibid., ex viii., p. 445. Falkenberg u. Marchand. Ibid., cxxiii., p. 579. Neuberger. Ziegler's Beitriig zur path. Anat., vi., p. 429. Leutert. Fortschritte der Med., 1895, p. 89. Wassilieff. Zts. f. phys. Chem., vi., p. 112. Bohm. Ibid., xv., p. 1. Welander. Arch. f. Derm. u. Syph., xxvi., p. 331. Pinner. Therap. Monateh., 1889, p. 320. IRON. 655 Lewin. Berl. klin. Woch., 1895, p. 245. Paton. Brit. Med. Journ., 1886, i., p. 433. Kuperwasser. Arch, des Scienc. biol., vi., p. 325. Neumann. Practitioner, vii., p. 279. Piccardi. Arch. f. Derm. u. Syph., xli., p. 177. Winternitz. Arch. f. exp. Path. u. Pharm., xxv., p. 225. Ludwig u. Zillner. Wien. klin. Woch., 1889, p. 857. Wolff u. Necja. Deutsch. med. Woch., 1885, p. 847. Paschkis u. Vajda. Wien. med. Presse, 1881. Schuster. Deutsch. med. Woch., 1883, p. 193 ; 1884, p. 279. Dreser. Arch. f. exp. Path. u. Pharm., xxxii., p. 456. Quincke. Munch, med. Woch., xliii., 1896, p. 854. Liebermann. Pfl tiger's Arch., liv., p. 573. Koch. Mittheil. a. d. Gesundheitsamte, i., p. 234. Geppert. Berl. klin. Woch., 1889, p. 789 ; 1890, p. 246. Gottstein. Therap. Monatsh., 1889, p. 102. Cathelineau. Arch. gen. de-Med., clxxiv., p. 38. Schumacher. Arch. I. Derm. u. Syph., xliv., p. 189. Stockman and Charteris. Journ. of Path, and Bact., 1903, p. 204. Wickham, Touton, Lieven, etc. Practitioner, July, 1904. III. IRON. Iron differs from the other heavy metals in being essential to the life of many, perhaps all, forms of protoplasm. In the vertebrates this is obscured by the fact that most of the iron is contained in the haemo- globin of the blood, and its importance in the other tissues is generally ignored. In the invertebrates, however, in many of which no corre- sponding compound exists in the blood, considerable amounts of iron are found in the tissues, and there is no question that throughout the animal kingdom iron is essential to living matter, quite apart from its special relation to the blood in the vertebrates. Molisch has shown that it is also necessary for the development of the lower vegetable forms, and it has been found that in its absence the higher plants fail to form chlorophyll, although iron is not actually contained in the latter as it is in haemoglobin. The iron combinations are generally divided into two classes in- organic and organic. 1 In the former of these iron is contained in the ordinary salt form, is dissociated in solution, and can be recognized by such tests as the black precipitate with ammonium sulphide, and the blue precipitates with the ferrocyanide or ferricyanide of potassium. In organic iron these tests fail, or are only elicited after prolonged contact, as the iron ion is less readily dissociated. Examples of inorganic iron are the chlorides, acetates or sulphates, while the best type of organic iron is haemoglobin, though numbers of others exist in the tissues. Between the ordinary salts of iron and haemoglobin and its allies there exists a number of compounds which are stained black by ammonium sulphide after prolonged contact, and which it is impossible to class either as organic or inorganic. 111 Organic" and "inorganic" are here used in a special meaning, and have no reference to the combination to which iron is attached, but to the method of attach- ment. Thus the acetate and albuminate of iron are both classified among the inorganic iron compounds, because they are capable of dissociation, and the iron is precipitated by ammonium sulphide. " Masked iron" is a preferable term for "organic iron," but has not been so widely used. 656 THE HEA VY METALS. When such a salt as the perchloride is added to a solution of proteid, it precipitates it at once in the form of iron albuminate. This insolu- ble body is also formed in the living tissues when the perchloride is brought in contact with them, and forms a protective coating on the surface. Iron has no such relation to the proteids as mercury, and does not corrode them of itself, any destruction which may be caused by such compounds as the perchloride being due to the acid constituent and not to the metallic ion. The albuminate is not so flocculent as that of mercury, and tends to protect the tissues from the acid, so that the corrosion of iron compounds is limited to the surface. The double salts of iron, the albuminous compounds, and organic iron do not pre- cipitate proteids, and are therefore neither irritant nor astringent aa long as they maintain their original form and are not decomposed into simple salts. Symptoms. Inorganic iron compounds, of which the perchloride may be taken as a type, have an astringent, metallic, or often acid taste, but in ordinary doses induce no further symptoms. If swal- lowed in large quantities, they cause pain and uneasiness in the stom- ach, nausea, vomiting and often purging, with all the ordinary symp- toms of acute gastro-intestinal irritation. General weakness and even collapse may be induced, but are manifestly secondary to the gastric and intestinal effects, and no symptoms which can in any way be at- tributed to the absorption of iron have been observed in either man or animals. The prolonged use of inorganic iron is frequently followed by some dyspepsia, and by constipation and colic, which are obviously due to the continued astringent action on the stomach and bowel. Other symptoms observed occasionally are blackness of the teeth and tender- ness in the gums, which may be due to the acid contained in many iron preparations ; the blackening of the teeth has been supposed to be due to the tannic acid of the food precipitating the inky black tannate of iron, or to the sulphide of iron being formed by the action of the hydrogen sulphide present in carious teeth. According to Buzdygan, the iron preparations increase the secretion of hydrochloric acid in the stomach, and may thus lead to hyperacidity, or aggravate it if already present. In artificial digestion, the salts of iron with organic acids are said to hinder the process more than those with inorganic acids, the ferric salts more than the ferrous, and the insoluble preparations least of all. The digestion of starch is almost unaffected by the pres- ence of iron. Iron given by the mouth induces leucocytosis (Pohl), and does not affect the amount of double sulphates excreted in the urine, so that it has no antiseptic action in the bowel (Morner). Some symptoms from the circulation are sometimes said to arise, but are for the most part subjective, and seem to be handed down by tradition rather than really observed. These are a feeling of congestion, fulness and heat in the head, and haemorrhages from the nose, throat and lungs, especially in phthisis. If these symptoms are not entirely imaginary, they are to be IRON. 657 attributed to some reflex from the stomach and intestine and not to any direct action of iron on the heart or vessels. When these astringent preparations are injected into the blood vessels in animals, they coagulate the proteids and cause thrombosis but no real symptoms of iron poisoning. Fatal thrombosis has been observed in patients from the injection of the perchloride into the uterus, and also into nsevi. The hypodermic injection of these salts causes some pain and swelling, but no further symptoms follow, and the iron is found for the most part deposited in an insoluble form at the point of injection. The General Symptoms of iron are obtained only by the intravenous in- jection of double salts, such as the tartrate of iron and sodium, which do not coagulate the blood, and at the same time are capable of freeing the iron ion in the tissues. Such salts as the ferrocyanides or ferricyanides on the other hand leave the body as such, and the iron ion is not liberated, so that no iron symptoms are induced. Meyer and Williams found that the double tartrate caused in the frog slowness and clumsiness in movement, which gradually developed into complete paralysis of the central nervous system. The heart seemed to be little affected, but the skeletal muscles were some- what less irritable than usual after death. In mammals, the symptoms of iron poisoning were often very late in appearing, and began with some acceleration of the breathing, which later became slow and dyspnoeic ; vomiting and diarrhoea often followed, and blood was sometimes seen in the evacuations of the stomach and bowel. Increasing weakness was followed by central paralysis and death, accompanied by weak convulsive movements. The heart seemed little affected, although the blood-pressure fell rapidly towards the end. Post-mortem, the mucous membranes of the stomach and intestine were found swollen and congested, and often contained numerous small blood extravasations. Kobert found that repeated injection of small quantities of the citrate of iron induces congestion of the kidney and the ap- pearance of casts and albumin in the urine. In acute poisoning the alka- linity of the blood is reduced owing to the excess of lactic acid formed. Iron, like the other heavy metals, would therefore seem to have a specific irritant effect on the intestinal and gastric mucous membrane, and to a less extent on the kidney. In addition, it depresses and eventually paralyzes the central nervous system, but it is impossible to state how far this is due to direct action, and how far it is secondary to the action in the alimentary canal. According to Kobert, iron perfused through the vessels has no effect on their calibre except in large doses, when it dilates them. The astringent action is due, therefore, to the precipitation of the proteids, and not to con- striction of the vessels. Apart from irritation of the stomach and intestine, no symptoms are induced by iron given by the mouth, because it is absorbed too slowly and in too small amount, and perhaps in a form which has little tendency to cause them. The Absorption of Iron has been a subject of discussion only during the latter half of the last century, for up to that time it had been assumed that it passed into the tissues with comparative ease, and was there formed to haemoglobin. In this way was explained its effect in anaemia, particularly in the form known as chlorosis, in which there is a deficiency of haemoglobin rather than of blood cells. The benefit accruing from the use of iron salts in this disease has been attested by so many generations of physicians that only the most skeptical can have any doubt on the subject. The first to question this explanation of the action of iron in chlorosis was Kletzinsky, who formulated a 42 658 THE HEAVY METALS. theory of its action, which was soon forgotten, however, and only became popularly known when it was resuscitated by Bunge. This explanation, which is generally stated as Bunge's theory, has been widely held during the last few years, but has now been abandoned by almost all its former supporters including its author, who has been compelled to admit not only that iron salts are absorbed but that their administration leads to an increased formation of haemoglobin. No account of the action of iron would be complete, however, without reference to an explanation, which has at least had the effect of establishing a number of facts regarding the fate of iron in the body, and also the less desirable result of increasing to a considerable extent the number of pat- ented preparations containing iron. Shortly stated, Bunge's theory is that in ordinary conditions a certain amount of iron is lost by the body constantly through the excretions, and this loss is made up by the absorption of the iron contained in the food. This food-iron consists wholly of organic iron, that is, of iron combined in such a way that sulphides attack it with difficulty ; an example of such organic iron is the haematogen of the yolk of egg. In normal individuals the food-iron is sufficient to replace that lost by excre- tion, but in chlorosis the presence of large amounts of sulphides in the in- testine causes the food-irons to be decomposed to ferric sulphide, which is insoluble and unabsorbable. When the ordinary inorganic iron prepara- tions are administered in these cases, they are not taken up in place of the food-irons ; but, by forming sulphide in the intestine, they remove the sulphuretted hydrogen, and prevent the decomposition of the food-irons, which thus remain capable of being absorbed. Bunge and his followers went on to state that inorganic iron is never under any circumstances ab- sorbed by the normal epithelium, but that when large quantities are admin- istered, they tend to corrode the walls of the stomach and intestine, and are thus absorbed to some extent. Even then, however, they are incapable of being formed to haemoglobin, the animal body being able to perform only the last steps of this synthesis, after the plants have formed the simpler types of organic iron. This theory now possesses only historical interest, so that it is unnecessary to enumerate the arguments brought against it. It may be sufficient to state that if the ordinary preparations of iron acted only by binding the sulphides of the intestine, various other metals would be equally efficient in chlorosis ; iron would not be beneficial injected hypoder- mically, and iron sulphide given so as to escape the action of the gastric juice would be equally useless. It is found, however, that no other metal can replace iron in chlorosis ; that iron injected hypodermically is curative in chlorosis, and that the sulphide administered so as to reach the intestine unchanged, acts as well as other preparations (Stockman). Finally, it has been shown that ordinary preparations of iron are absorbed. Driven from their former position that inorganic iron is not absorbed by the intestine, the advocates of the use of organic iron in chlorosis have at- tempted to make a further stand by asserting that, although the ordinary preparations are absorbed, they are not used in the formation of haemoglobin, but after a more or less prolonged stay in the liver and other organs, are excreted. This statement is refuted, however, by several researches, in which the addition of inorganic iron to food deficient in iron (milk), or entirely free from it, prevented the anaemia which was observed in animals fed on the same food, but without iron. Finally Abderhalden, the latest ex- ponent of Bunge's views, finds that inorganic iron increases the haemoglobin of the blood, but suggests that it may do so indirectly by taking the place of the food-iron which supplies the needs of the tissues, the food-iron then being formed to haemoglobin ; he fails to supply any arguments in support of this theory, which it is therefore unnecessary to discuss. IEON. 659 The chief difficulties in following the course of iron in the body are due to its being present in all the tissues and secretions normally, and to the very small quantity which is contained in ordinary food, and which is essential to the maintenance of health. About 2J-3J G. (40-55 grs.) of iron are estimated to be present in the tissues of a healthy human adult, the greater part of it existing in the form of haemoglobin in the blood. Formerly it was believed that some 50 mgs. (1 gr.) of iron were taken in the food per day, but Stockman and Greig have recently shown that this estimate is much too high, and that an ordinary dietary provides only about 5-10 mgs. (-j 1 ^ J gr.) of iron per day ; they found in one case that even 3-5 mgs. (^V~lV & r ") were sufficient to preserve the iron equilibrium. About the same amount of iron is excreted per day, chiefly in the faeces, to a much smaller extent in the urine. When additional iron is supplied to the body, either as inorganic or as organic iron, much the greater part of it reappears in the stools. This does not necessarily entail that all of it has passed through the bowel unabsorbed, for it is now perfectly certain that iron is excreted through the intestinal epithelium, so that some of the iron of the stools may have been absorbed and reexcreted. The strongest argument cited by Bunge in support of his theory was that inorganic iron, given by the mouth, did not increase the iron of the urine. He assumed that any iron absorbed would necessarily appear in course of time in the urine, but this has been shown to be incorrect by a whole series of in- vestigations. When iron salts such as the double tartrate are injected into a vein, they soon disappear from the blood, but only some 2-5 per cent, of the quantity injected reappears in the urine, the rest being withdrawn from the blood and stored up in the cells of the liver and spleen, and perhaps in the bone-marrow. Thus even if iron is ab- sorbed in the intestine, it is improbable that it will reappear in the urine in appreciable quantity, for supposing 10 mgs. to be taken up, 2 per cent, of this would represent only ^ mg. and this lies within the limits of error of estimation. In addition, it seems probable that when iron enters the blood slowly and in small quantities, even a less pro- portion of it is excreted in the urine than when larger quantities are injected suddenly. On the whole the evidence goes to show that 0.5-1.5 mgs. of iron are normally excreted in the urine in 24 hours, and that the administration per os of iron preparations, whether organic or inorganic, does not affect this amount. The fact that an iron preparation given by the mouth does not increase the iron in the urine is therefore no evidence that it has not been absorbed from the stomach. Iron injected into the veins of normal animals is stored up in the liver and spleen, but is slowly taken up from these organs again, and is excreted by the epithelium of the caecum and colon. When iron is given by the mouth, therefore, it may either pass along the canal and be thrown out in the faeces, or it may be absorbed, make a stay in the liver, be excreted in the large intestine, and again appear in the stools. The comparison of the iron in the food and in drugs with that of the 660 THE HEAVY METALS. stools therefore gives no clue as to how much has been absorbed, and how much has simply passed through the intestine. But the passage of iron from the liver to the intestine is a somewhat slow process, and it is therefore possible to detect the excess of iron in the liver. This has been done repeatedly by the following method. Young animals of the same litter fed on milk have approximately the same amount of iron in the liver. If one be fed on milk only, the other on milk to which iron is added, the .liver of the latter is found to contain more iron than that of the control. Other investigators have fed animals (rats or mice) on food that is practically free from iron, have killed them and estimated the iron in the whole body apart from the alimentary tract and compared it with that of animals treated in the same way except that iron was added to the food. The latter group contains much more iron than the control group fed on iron-free food, and in general presents a much more healthy and normal ap- pearance. Finally, attempts have been made to follow the iron in its course through the tissues. This is possible by the histological examination of tissues soaked in ammonium sulphide solution, in potassic ferrocy- anide and hydrochloric acid, or in haBmatoxylin, as these form black or blue precipitates with most forms of iron, but leave the haemoglobin unaffected. When animals are given iron preparations, and are 'then killed, and their organs stained by these reagents, the mucous mem- brane of the stomach and of the greater part of the small intestine gives no coloration, but the epithelium of the duodenum and the upper part of the jejunum is found to contain numerous granules of iron. These granules may be traced to the mesenteric lymph glands, are found in large numbers in the spleen around the corpuscles, to a much smaller extent in the liver, and in the cortex of the kidney. If, however, the animal be kept for some days after the iron is given, the reaction in the duodenum, spleen, and mesenteric glands is less intense, while the liver gives much more distinct evidence of containing iron, and the epithelial cells of the large intestine and caecum also give a strong reaction. This is interpreted to mean that iron is absorbed by the duodenum and is first stored in the spleen, but later finds its way through the blood vessels to the liver, where it rests again for some time, to be eventually taken up again by the blood and excreted into the large intestine and the caecum. There is some question as to whether the lymph vessels are involved in the absorption of iron and the most recent investigators have failed to find it in the thoracic duct and accordingly hold that it is absorbed from the intestine into the blood vessels directly. The iron stored in the liver does not escape by the bile as might be anticipated. A small percentage of iron is a constant constituent of this fluid, but is not increased by iron given by the mouth or intravenously. Nothing is known with certainty regarding the form in which iron is absorbed. It is assumed that in the stomach almost all the prepa- IRON. 661 rations form chlorides to a greater or less extent, 1 are then changed into albuminates, and in this form pass into the duodenum, where they may be absorbed in solution, or may be precipitated and taken up as solids by the epithelial cells and the leucocytes. In the liver it seems likely that the absorbed iron is changed to hepatic ferratin, and that it is stored in this form. Several other iron compounds have been found in the liver, and iron undoubtedly undergoes a number of synthetic processes there. It must not be inferred from the foregoing that all of the inorganic iron swallowed is taken up by the intestinal epithelium. It is quite impossible to form even approximate estimates of the amount that is really absorbed and made use of by the tissues, but the probability is that only a small percentage is really taken up ; the rest passing through the intestine and being thrown out in the stools. It is often stated that the iron stools are dark or black in color, from the sulphide present, but this seems to be seldom the case when they are passed, although they assume a darker gray or grayish black color in the air from oxidation. The iron is contained in them only to a small extent as the sulphide, some of the rest probably being albuminate. To sum up what is known regarding the fate of the iron preparations, they are partially formed to the chloride and then to the albuminate in the stomach, pass into the duodenum, from which the great bulk is car- ried on into the lower parts of the intestine, while some is absorbed by the epithelium and leucocytes in solid form and perhaps in solution. It is then deposited in the spleen, where it may undergo some changes in form, is later taken up by the blood and deposited in the liver and perhaps in the bone marrow. Where the supply of iron has been inadequate for the formation of haemoglobin, the originally inorganic iron is probably worked into higher forms and eventually into haemo- globin in the liver, and it seems likely that ferratin is one of the intermediate steps in this synthesis. When there is no deficiency of iron for the formation of haemoglobin, the liver slowly yields its store of iron to the blood, which carries it to the caecum and large intestine, by the epithelium of which it is finally excreted. It is to be noted that the iron absorbed does not increase the amount of iron in the urine, bile or other excretions. The investigations on which this sketch is founded have been completed only in the last few years, and establish finally the truth of the position held by the older physicians and indeed by the clinicians of this later time also, that inorganic iron follows the same course in the tissues as food- iron, although possibly more of the latter is absorbed. But this explanation of the iron action does not cover all the diffi- culties of the case. Many cases of chlorosis recover without inorganic iron under hygienic conditions, such as rest, and particularly when foods rich in iron are prescribed, this being exactly what is to be ex- pected on the theory that inorganic iron merely takes the place of the 1 According to several of the older authors the ferric salts are changed to ferrous in the stomach. 662 THE HEAVY METALS. deficient food-iron. But many chlorotic patients show little or no improvement when treated with foods containing iron, even when there is no question that the iron supplied daily in food form is sufficient for the needs of the economy, and chlorosis even appears in individuals who have never suffered from any deficiency of food-iron. Yet many of these cases recover rapidly under inorganic iron. V. Noorden has attempted to explain this by supposing that inorganic iron when absorbed acts as a stimulant to the blood-forming organs, while food-- iron has no such property. And some indications of abnormal activity of the bone-marrow cells have been observed in animals supplied with inorganic iron ; this may not be the effect of stimulation in the ordi- nary sense of the word, however, for it may be explained by the un- usual abundance of the materials necessary to their activity. The difference in the effects of the irons of the food and of the inorganic preparations may be due to the fact that food-iron is always accom- panied by a large amount of colloid material, which may materially delay its absorption while inorganic iron on the other hand is much less completely enveloped, and may be more easily absorbed. In ad- dition, the iron preparations are given in much larger amounts than the food-irons. When 10 mgs. (food-iron) are taken per day, only a small proportion (e. g., 5 mgs.) may be absorbed, and this may be insufficient to supply the needs of the body, but if some hundreds of milligrams of inorganic iron be added, the proportion absorbed will be amply sufficient. The same effect might be obtained by the same amount of food-iron, but this is only to be obtained by giving more food than can be digested. Iron is not absorbed from the unbroken skin, and the iron and steel baths are therefore of no value in themselves in the treatment of anaemia. Therapeutic Uses. Iron is most frequently used in the treatment of Chlorosis, which in a large proportion of cases recovers entirely under it. Some cases, however, improve somewhat under iron, but relapse when it is left off, and a certain number of patients show no improve- ment whatever under it. These last are not generally regarded as suffering from chlorosis proper, but from a more malignant form of anaemia. A number of symptoms which are due to chlorosis, and which are often more prominent than the original disease, are also re- lieved or entirely removed by iron. Thus gastric catarrh, amenorrhoaa, or oedema may disappear under it, but in these cases the symptoms are chlorotic in origin, and the improvement is due to the increased haemoglobin, and not to the direct action of iron on the stomach, uterus or circulation. In chlorosis, the iron is generally given in small doses, at any rate at first, and the less astringent preparations are preferred by most clinicians, although some still advise the perchloride. When chlorosis is complicated with gastric catarrh, some authorities advise that the latter be treated before the general condition, as iron in itself is liable to irritate the stomach. In many cases, however, the catarrh is secondary to the chlorosis, and can only be treated successfully by IRON. 663 improving the condition of the blood ; the iron preparation here ought to be mild and not irritating. In chlorosis the tendency to constipa- tion may be increased by iron, and a purge is often required, such as the iron and aloes pill, which is particularly recommended when chlo- rosis is attended by amenorrhoaa. Iron is of less value in other forms of anaemia, although it is often prescribed and may be followed by some improvement. Thus it may be administered during convalescence from acute disease, such as typhoid fever, or nephritis, and in the anaemia induced by profuse haemorrhage, iron often seems to accelerate the recuperation of the blood. It is often prescribed for the cachexia of malaria, syphilis and other chronic diseases. Iron is said to be contraindicated where there is fever, in plethoric individuals with a tendency to haemorrhages, and in some forms of heart disease. In these conditions the iron preparations can harm only from a reflex induced from the stomach, as the small quantity of iron absorbed is incapable of producing any effects in the tissues. In phthisis, it is very generally credited with causing haemorrhage from the lungs, but it may be questioned how far this apprehension is based on observation, and how far it is a relic of old and forgotten theories of the action of iron. It has to be given with caution here in order to avoid irritation of the stomach and dyspepsia, and in the presence of gastric catarrh from any cause, its effects have to be watched care- fully. Some of the older authorities advise iron to be given in large quan- tities, but the dose has been reduced of late years to about 0.1-0.2 G. (2-3 grs.) three times a day. It is given after meals in order to avoid the irritant action on the stomach as far as possible. It is to be noted that on giving 0.1 G. of iron three times a day, about thirty times as much iron is given as is required normally in food, so that the chlorotic receives more iron per day than a workman in a month. Iron is occasionally injected hypoderinically, with the object of avoiding the irritation of the stomach, but this procedure is painful and causes some swelling and irritation, which lasts twenty-four hours or more. Most of the salts are precipitated at the point of injection, but some, such as the citrate, are taken up by the blood at once ; the danger of renal irritation, anticipated by Kobert, does not seem to. arise if small quantities are used. The citrate and pyro-phosphate in 5 per cent, solution have been used in this way, 0.05-0.1 G. (1-2 grs.) of the salt being injected daily. The hydrate and oxide have also been injected, suspended in salt solution, but are somewhat more irri- tant, while the peptonate is recommended as being almost devoid of irritant qualities. Iron has been recommended in erysipelas, but has proved valueless in the hands of most investigators. Some of the iron salts are employed as Astringents, the most popular preparations for this purpose being the ferrous sulphate, which has been used to some extent in diarrhoaa, and also externally. The perchloride is perhaps the best Styptic of its 664 THE HEAVY METALS. class. When applied to a bleeding point, it precipitates the proteids of the blood plasma, and thus forms an obstruction to the flow of blood similar to that caused by clotting, although no fibrin, but only a mass of iron albuminate, is formed by the perchloride. This styptic action is of value in capillary and recurrent haemorrhage, while in bleed- ing from an artery, the ordinary surgical methods are of course pre- ferred. The chloride arrests hemorrhage only when it can be brought into actual contact with the bleeding point, and where this is covered by a large mass of semicoagulated blood, the treatment is of no avail, as it simply forms the albuminate with the blood with .which it comes into contact first, and this may be far from the actual point of rupture. As an application to the stomach and bowel in hemorrhage from these parts, the perchloride is unlikely to prove successful, while in bleed- ing from the nose, or gums, or after the extraction of a tooth, it is more reliable. It has been injected into the uterus in haemorrhage, into nevus in order to cause coagulation and subsequent cicatrization of the tissue, and into aneurisms. This is a very dangerous treat- ment, however, for several cases of fatal embolism have arisen from the precipitated albuminate being carried off in the veins. Perchloride of iron solution has been sprayed into the air passages in hemoptysis, but if sufficiently concentrated to coagulate the blood at the bleeding point in the lungs, it would certainly induce irritation and coughing. The perchloride is, of course, valueless in hemorrhage from internal organs, for in the first place, very little of it is absorbed, and in the second place, what does pass into the tissues is already in proteid com- bination, and therefore incapable of coagulating the blood. The same objection applies to the alleged astringent effect of iron in nephritis. It is possible that iron may lessen the albumin in the urine in these cases, although the clinical evidence is contradictory on the subject, but it is absolutely certain that it does not do so by any local action on the albumin in the kidney. The sulphate of iron is used as a disinfectant for sewage. It acts here merely by precipitating the proteids, which carry down the bac- teria mechanically. The proteids of the sewage may be increased by the addition of blood before the sulphate is applied. The sulphate of iron is used, because it is cheaper than the other salts of the heavy metals. PREPARATIONS. Ferri Chloridum (U. S. P.), ferric chloride (Fe 2 Cl 6 -fl2H 2 O), orange yellow crystals, with a strong astringent taste, very deliquescent in air, soluble in water and alcohol. Liquor Ferri Chloridi (U. S. P.), a solution of ferric chloride containing about 37.8 per cent, of the anhydrous salt or about 13 per cent, of iron. TINCTURA FERRI CHLORIDI (U. S. P.) is formed from the liquor by dilut- ing it with 3 parts of alcohol. 0.5-2 c.c. (8-30 mins.). Liquor Ferri Perchloridi Fortis (B. P.) is formed by dissolving iron in hy- drochloric acid, and contains 22 per cent, of iron. It is an orange-brown fluid, with a strong astringent taste. IRON. 665 Liquor Ferri Perchloridi (B. P. ) and TINCTURA FERRI PERCHLORIDI (B. P.) are formed by diluting the strong liquor with 3 times as much water, and with two parts of water and one of alcohol respectively. 5-15 mins. The chloride is used as a styptic either as the Liquor Fortis (B. P.) or in a very much stronger form, prepared by allowing the crystals to deliquesce. A plug of cotton-wool steeped in the solution is used to stop bleeding after the extraction of teeth, and the liquor has been injected into the uterus in hemorrhage, and into aneurisms and nsevi. When diluted it may be used as a gargle, but has a disagreeable, inky taste, and attacks the teeth. The tincture is very commonly used in the treatment of chlorosis. It ought to be taken in a glass of water, and through a quill or glass tube, in order to avoid injury to the teeth. Liquor Ferri Nitratis (B. P.) contains 3.3 per cent, of iron. 5-15 mins. Used as an astringent to a limited extent. Liquor Ferri Tersulphatis (U. S. P.), Liquor Ferri Persulphatis (B. P.), a so- lution of ferric sulphate (Fe 2 (SO 4 ) 3 ), is used only for the preparation of other iron salts. Liquor Ferri Subsulphatis (U. S. P.), Monsel's solution, an aqueous solu- tion of basic ferric sulphate of variable chemical composition, and containing about 13.8 per cent, of metallic iron. 0.2-0.6 c.c. (3-10 mins.). Used as an astringent gargle, and in general like the chloride. FERRI SULPHAS (U. S. P., B. P.), ferrous sulphate (FeSO 4 -f 7H 2 O), large, pale, bluish-green crystals with a saline, astringent taste, soluble in water, insoluble in alcohol, and unstable in moist air. 0.05-0.3 G. (1-5 grs.). Ferri Sulphas Granulatus (U. S. P.), recrystallized ferrous sulphate in very small crystals. 0.05-0.3 G. (1-5 grs.). Ferri Sulphas Exsiccatus (U. S. P., B. P.), dried ferrous sulphate (2FeSO 4 + 3H 2 O), ordinary sulphate from which most of Lie water of crystallization has been driven off by heat. A grayish-white powder resembling the ordi- nary sulphate in its solubility. 0.03-0.2 G. (J-3 grs.). Ferri et Ammonii Sulphas (U. S. P.), ammonio-ferric sulphate or ammonio- ferric alum (Fe 2 (NH 4 ) 2 (SO 4 ) 4 +24H 2 O), is a double salt forming pale violet crystals with an acid astringent taste soluble in water, not in alcohol, 0.3-0.6 G. (5-10 grs.). The sulphate of iron is very astringent, though less so than the ferric salts. It is used as an astringent application to mucous membranes, such as the eye, mouth, urethra, more rarely internally in anaemia, although it is less irritant than the chloride. The Pil. Aloes et Ferri (U. S. P., B. P.), which is used very largely in amenorrhoea and in chlorosis with constipation, contains dried sulphate of iron. Dose, B. P., 4-8 grs. Ferrum (U. S. P. , B. P.), metallic iron in the shape of fine wire is used only to form other preparations. FERRUM REDUCTUM (U. S. P.), FERRUM REDACTUM (B. P.), reduced iron, a very fine grayish-black, lustreless powder, without taste, insoluble in water or alcohol, soluble in acid. It consists of metallic iron, with a small amount of the magnetic oxide. 0.05-0.3 G. (1-5 grs.). Trochiscus Ferri Redacti (B. P.), each contains 1 gr. of reduced iron. FERRI CARBONAS SACCHARATUS (U. S. P., B. P.), saccharated ferrous car- bonate, is formed by precipitating ferrous sulphate with sodium bicarbonate (ammonium carbonate, B. P.), washing the precipitate and adding sugar. It contains ferrous carbonate along with some ferrous sulphate and sodium bi- carbonate (U. S. P.), and is a greenish-brown powder, which rapidly oxidizes in the air, and has a sweetish, astringent taste. The carbonate is a very unstable body, and on keeping is slowly transformed to ferric hydrate (Fe 2 (OH) 6 ). The sugar is added in order to retard this oxidation, but the carbonate ought not to be dispensed unless it is of recent preparation. 0.6- 2 G. (10-30 grs.). 666 THE HEAVY METALS. PILULE FERRI CARBONATIS (U. S. P.), PILULA FERRI (B. P.), ferruginous or chalybeate pills, BLAUD'S PILLS, are prepared in the same way, by the ac- tion of ferrous sulphate and carbonate of potash or soda. Sugar, tragacanth and glycerin are added ; they ought to be freshly prepared in order to avoid the formation of the hydrate. Each pill (U. S. P.) contains about 0.06 G. (1 gr.) of iron, that is, 5 grs. contain about 1 gr. A method of keeping the carbonate and the sulphate apart until actually swallowed has been adver- tised, the two being given in a capsule, but being separated by a membrane which is dissolved off in the stomach. This same effect would be obtained by giving them entirely separate, and it is extremely improbable that the car- bonate is formed in the acid contents of the stomach. 1-5 pills U. S. P. , 5- 15 grs. B. P. Massa Ferri Carbonatis (U. S. P.), Vallets' Mass, is formed by the action of ferrous sulphate and sodium carbonate. Sugar and honey are added to the precipitate to form a mass of the proper consistency for pills. This preparation has never enjoyed the popularity of Blaud's pills and is super- fluous. 0.2-0.3 G. (3-5 grs.). MISTURA FERRI COMPOSITA (U. S. P., B. P.), Griffith's mixture, is formed by mixing ferrous sulphate, potassium carbonate, myrrh, sugar, spirits of lavender (nutmeg, B. P.) and rose water. The ferrous carbonate (FeCO 3 ) is precipitated and the mixture has therefore to be shaken before taking, and ought to be freshly prepared. 15-30 c.c. (|-1 fl. oz.). Reduced iron and the four carbonate preparations are used exclusively in the treatment of ansemia. They are practically devoid of irritant properties, and are among the best of all the iron preparations for this purpose. The Blaud's Pills have in particular a well merited reputation in the treatment of chlorosis and of chlorotic amenorrhoea. Another preparation used for this purpose but not official is Ferrum Dialysatum in which a considerable amount of iron oxide is kept in a semi-colloid state dissolved in a minimum amount of the chloride. It tastes of iron but is not astringent. Ferri Hydroxidum (U. S. P.), ferric hydrate, or hydroxide (Fe 2 (OH) 6 ), a brownish-red, pasty mass, insoluble in water or alcohol, but soluble in hydro- chloric acid, is used almost exclusively in the treatment of arsenic poisoning, as it is supposed to retard its absorption in the stomach. It ought to be freshly prepared, otherwise it forms particles which combine with greater difficulty with the poison. Ferri Hydroxidum cum Magnesia (U. S. P.), is formed by precipitating ferric sulphate by magnesia and is used in arsenic poisoning and known as the arsenic antidote. Both of these preparations have to be given freely in arsenic poison- ing, at least 15-20 G. ( oz.). The remedy is harmless in itself, but its efficacy is very doubtful. Liquor Ferri Acetatis (B. P.), an aqueous solution of the acetate (Fe 2 (C 2 H 3 O 2 ) 6 ), containing about 31 per cent, of the salt or about 7.5 per cent, of iron. 0.3-1 c.c. (5-15 mins.). Ferri Citras (U. S. P. ), transparent, garnet- red scales with a slight iron taste. 0.05-0.3 G. (1-5 grs.). Ferri Phosphas (B. P.), a powder containing not less than 47 per cent, of hy- drous ferrous phosphate (Fe 3 (PO 4 ) 2 8H 2 O), with ferric phosphate and some iron oxide. It is a slate-blue, amorphous powder, insoluble in water. 5-10 grs. Syrupus Ferri Phosphatis (B. P.). 1 fl. dr. represents 1 gr. of anhydrous ferrous phosphate. -1 fl. dr. Ferri Phosphas Solubilis (U. S. P.). The phosphate of iron is insoluble in itself, but is rendered soluble by the presence of sodium citrate thin, green scales with a saline taste, insoluble in alcohol. 0.1-0.5 G. (2-8 grs.). Ferri Pyrophosphas Solubilis (U. S. P.), like the phosphate, is rendered soluble by sodium citrate, and resembles it in its appearance and solubility. 0.1-0.5 G. (2-8 grs.). Ferri Hypophosphis (U. S. P.) (Fe 2 (PH 2 O 2 ) 6 ), a white powder, odorless and nearly tasteless, almost insoluble in water, but dissolved by solutions of the alkali citrates. 0.3-1 G. (5-15 grs.), in pill. IRON. 667 Pilultz Ferri lodidi (U. S. P.), each contains 0.04 G. of iron. 1-2 pills. Syrupy s Ferri lodidi (U. S. P., B. P.) contains about 1.8 per cent, of iron. 2-4 c.c. (i-1 fl. dr.). Ferri Arsenas (B. P.), iron arsenate, consists of ferrous arsenate (Fe 3 (AsO 4 ) 2 , 6H 2 O), with ferric arsenate and some iron oxide, and forms a tasteless, amorphous powder of a greenish color, insoluble in water, TS~i g r - These preparations have all been prescribed to a greater or less extent in the treatment of anaemia, the lactate, phosphate and pyrophosphate being perhaps more widely used than the others. It is needless to repeat that the valerianate is not of greater value in hysteria than the other preparations, as valerianic acid is useless in this condition. The iodide has been advised in order to combine the effects of iodide and iron, but the iodide given in this form is in much smaller quantity than that found necessary in the iodide of potassium treatment, and it. seems open to question whether the improvement is not due to the iron only. The hypophosphite is also used in cachexia, in order to combine the hypophosphite and the iron effects. Ferri et Quininse Citras (U. S. P., B. P.), thin scales of a reddish-brown color, and of a bitter, iron taste, slowly soluble in water, partially soluble in alcohol, containing 11.5 percent, of quinine and 14.5percent. of iron U. S. P. 0.3-0.6 G. (5-10 grs.). Ferri et Quininss Citras Solubilis (U. S. P.), thin scales of a greenish color and of a bitter, iron taste, easily soluble in water, only partially in alcohol. It contains the same amount of iron and quinine as the ordinary preparation. 0.3-0.6 G. (5-10 grs.). Ferri et Strychninse Citras (U. S. P.), thin, transparent scales of garnet-red or yellowish-brown color, readily soluble in water, containing about 1 per cent, of strychnine and about 16 per cent, of iron. 0.1-0.3 G. (2-5 grs.). Syrupus Ferri, Quininse et Strychninse Phosphatum (U. S. P.), Syrupus Ferri Phosphatis cum Quinina et Strychnina (B. P.). 2-4 c.c. ($-1 fl. dr.). Glyceritum Ferri, Quinines et Strychnine Phosphatum ( U. S. P. ). 1 c. c. ( 15 mins. ). Elixir Ferri, Quinince et Strychnine Phosphatum (U. S. P.). 4 c.c. (1 fl. dr.). Ferri et Ammonii Citras (U. S. P., B. P.), thin garnet-red scales with an acid, iron taste, soluble in water and containing 16 per cent. iron. 0.3-0.6 G. (5-10 grs.). Ferri et Ammonii Tartras (U. S. P.), thin, transparent, garnet-red scales, very soluble in water and containing about 17 per cent, of iron. 0.3-0.6 G. (5-10 grs.). Ferri et Potassii Tartras (U. S. P.), Ferrum Tartar atum (&. P.) resembles the last preparation, but contains only about 15 per cent, of iron. 0.3-0.6 G. (5-10 grs.). Liquor Ferri et Ammonii Acetatis (U. S. P.), Basham's mixture, contains only a very small proportion of iron, along with acetic acid, ammonium acetate, aromatic elixir and glycerin. 15-30 c.c. (J-l fl. oz.). Vinum Ferri (B. P.). 1-4 fl. drs. Vinum Ferri Amarum (U. S. P.). 8-15 c.c. (2-4 fl. drs.). Vinum Ferri Citratis (B. P.), Vinum Ferri (U. S. P.). 4-15 c.c. (1-4 fl. drs.). The two wines of iron of the U. S. P. are practically identical except that the first contains the citrate of iron and quinine, the second, the citrate of iron and ammonium. Each is made up with tincture of sweet orange peel, syrup and white wine. The iron wine of the B. P. is formed by dissolving iron in sherry wine, the citrate of iron wine by dissolving the citrate in orange wine. The double salts of iron (scale preparations) and the wines are used to some extent in chlorosis, but more frequently in convalescence from acute fevers, which is often attended by anemia : in these cases the iron wines are often of considerable value. The double salts are not so liable to disturb the digestion as the other soluble preparations of iron, but are not superior to the carbonate preparations and the reduced iron in this respect. 668 THE HEAVY METALS. Iron is contained in many mineral waters, which are therefore advised in cases of anaemia. It is generally in the form of the carbonate, which is dis- solved by the excess of carbonic acid present, but becomes oxidized to the insoluble ferric hydrate in the air. The amount of iron contained is small, seldom being more than 0.1 G. per litre, but the treatment of chlorosis is unquestionably aided by change of scene and in particular by the high elevations at which many of these springs are situated, so that the suc- cess of treatment with these iron waters is perfectly intelligible. Bathing in iron water has no further action on the blood than ordinary baths, as no iron is absorbed. Many Proteid Compounds of iron have been introduced into therapeutics in the last few years, but few of them need be mentioned, as a large number of them promise to be relegated to merited oblivion in the near future. The albuminate of iron and the peptonate of iron are generally prepared by the action of the chloride on egg albumin or on peptone, and vary very consid- erably in the percentage of iron contained. In most of them the albu- minate or peptonate is accompanied by more or less perchloride and oxide. These preparations are not "organic " iron in the sense denned on page 659, for the iron can be split off easily, and is precipitated by sulphides almost as readily as the ordinary salts. The albumiuate and peptonate possess no advantage over the usual preparations, unless they prove less irritant to the stomach, and of this there is no satisfactory evidence. Soluble peptonateand albuminate of iron are put on the market by a number of manufacturers. Schmiedeberg found in the liver an iron compound which does not seem to resemble the ordinary salts, for it is only blackened by sulphides after sometime, and in other ways shows resemblances to the "organic iron," such as the hsematogen of the yolk of egg. It would seem to stand midway between the ordinary dissociable salts and hemoglobin, for it reacts to ammonium sulphide more tardily than the former, while the latter is not affected by this reagent. Schmiedeberg named this compound, which is an iron -containing proteid, Ferratin. He attempted to form a similar sub- stance synthetically from the white of egg, and obtained a body containing 6-8 per cent, of iron, which reacted similarly with sulphide, and which he failed to dissociate by electrolysis. Believing it to be identical with the hepatic ferratin, he advised its use in chlorosis as being a natural food iron. It is impossible to state from these reactions, however, that the two sub- stances the hepatic and the artificial ferratin are identical, and, in fact, Macallum finds that the former fails to give the haematoxylon test, while the latter yields it readily. Artificial ferratin is partially decomposed in the stomach into ordinary inorganic salts, but there seems reason to believe that it is absorbed more easily than the usual preparations, and it is not irritant to the stomach and does not often give rise to dyspepsia. On the whole, ferratin seems a good preparation for use in chlorosis, but possesses no such specific virtues as have been attributed to it by enthusiastic advocates, and it has the disadvantage of being very much more expensive than most other preparations. It is given in powder or pill, or in solution as a sodium compound, in quantities of 0.5-1.5 G. (8-20 grs.) per day. Carniferrin is an iron compound of carniphosphoric (phosphosarkinic) acid, which is obtained from beef extract. It contains 35 per cent, of iron, and seems to bear the same relation to the inorganic salts and to haemo- globin as artificial ferratin, for while it reacts slowly to sulphide, it gives the haematoxylon test. It has been highly recommended in chlorosis, as it does not irritate the stomach and is rapidly absorbed. It is given in doses of 0.5 G. (8 grs.) three times a day in powder, and like ferratin, is soluble in alkaline solutions. The hsematogen of the yolk of egg, another organic iron of the same type as ferratin and carniferrin, is obtained in too small quantity to be available for therapeutic use, but seems to be absorbed readily. IEON. 669 Other proteid compounds which have been advised are formed from yolk of egg or from casein, by the addition of iron salts. Blood has been used in therapeutics by uncivilized peoples since time unknown, and has also been recommended in modern medicine in the treatment of chlorosis, in which it is administered by the mouth, and also hypodermically, though the latter method is difficult to carry out aseptically. Haemoglobin has also been advertised largely of late years in a more or less impure form. In the stomach, haemoglobin, whether contained in blood or as crystals, is changed to haematin ; Abderhalden found that both haemo- globin and hsematin are absorbed and lead to an increase in the haemoglo- bin of the blood. Hsemol and hsemogollol are prepared from blood by agitat- ing it with zinc and with pyrogallol respectively, and have been strongly recommended by their discoverer, Robert, and by some clinicians, but have been found by others of less value than the old inorganic salts. The ' t organic ' ' iron preparations therefore seem to have little to recom- mend them as superior to the * ' inorganic, ' ' except that ferratin and carni- ferrin are probably more rapidly absorbed, and are less liable to cause dyspepsia than many of the older salts. Where there is special difficulty in administering the more commonly used forms, these two may be substituted for them with advantage, but they seem to be unnecessary in ordinary cases. In regard to the other preparations mentioned, further and impartial inves- tigation is required before their place in therapeutics can be determined. BIBLIOGRAPHY. Meyer u. Williams, Arch. f. exp. Path. u. Pharm., xiii., p. 70. Robert. Ibid., xvi., p. 361. Hamburger. Zts. f. phys. Chem., ii., p. 191 ; iv., p. 248. Bunge. Ibid., ix., p. 49 ; xiii., p. 399 ; xvi., p. 173 ; xvii., p. 63. Hdusermann. Ibid., xxiii., p. 555. Bunge, Quincke. Cong. f. inn. Med., 1895, p. 133. Marfori. Arch. f. exp. Path. u. Pharm., xxix., p. 212. Schmiedeberg. Ibid., xxxiii., p. 101. Gottlieb. Ibid., xxvi., p. 139. Zts. f. phys. Chem., xv., p. 371. Jakobj. Arch. f. exp. Path. u. Pharm., xxviii., p. 256. Socin. Zts. f. phys. Chem., xv., p. 93. Molisch. Sitzungber. Wien. Akad., ciii., 1894, Abt. i., p. 554. Kunkel Pfliiger's Arch., 1., p. 1 ; Ixi., p. 595. Stockman. Brit. Med. Journ., 1893, i., p. 881. Journ. of Phys., xviii., p. 484 ; xxi., p. 55 (with Greig). Macallum. Journ. of Phys., xvi., p. 268 ; xxii., p. 92. Woltering. Ztschr. f. phys. Chem., xxi., p. 186. Hall. Arch. f. Anat. u. Phys., 1894, p. 455 ; 1896, p. 49. Pohl. Arch. f. exp. Path. u. Pharm., xxv., p. 65. Gaute. Deutsch. med. Woch., xxii., pp. 289, 373 (1896). Zts. f. Biol., xxxv., p. 377. Hochhaus u. Quincke. Arch. f. exp. Path. u. Pharm., xxxvii., p. 159. Damaskin, Kumberg, Busch, Stender, Anselm, Samojloff. Arb. a. d. pharm. Instit. zu Dorpat, vii., viii., ix. Cloetta. Arch. f. exp. Path. u. Pharm., xxxvii., p. 69; xxxviii., p. 161 ; xliv., p. 363. Hofmann. Virchow's Arch., cli., p. 488. Filippi. Ziegler's Beitrage zur path. Anat., xvi., p. 462. Morner. Zts. f. phys. Chem., xviii., p. 13. Buzdygan. Wien. klin. Woch., 1897, p. 713. Voit. Zts. f. Biol., N. F., xi., p. 387 (1893). Glaevecke. Arch. f. exp. Path. u. Pharm., xvii., p. 466. Baumann. Journ. of Phys., xxix., p. 18. Tartakowsky. Pfliiger's Arch., ci., p. 423. V. Noorden. Berl. klin. Woch., 1895, p. 181. Hari. Arch. f. Verdauungskrank. , iv., p. 160. Abderhalden. Ztschr. f. Biologic, xxxix., pp. 113, 193, 487. Mulkr. Virchow's Arch., clxiv., p. 436. 670 THE HEAVY METALS. IV. LEAD. Lead is used to some extent in therapeutics, but its chief interest from a medical point of view lies in the frequency with which it gives rise to chronic poisoning, and in the diversity of the symptoms pre- sented in that condition. Solutions of lead salts precipitate albumin, and the precipitate is more dense and heavy than that of mercury, and less soluble in excess of the salt. This precipitate is formed when lead solutions are applied to the mucous membranes, and protects them from the penetration of the metal, so that lead is one of the least corrosive, and one of the most astringent of the heavy metals. This absence of corrosion is only in part due to the character of the precipitate, for lead forms insoluble and therefore non-irritant salts with two of the most corrosive acids, hydrochloric and sulphuric acids. The soluble nitrate of lead is comparatively irritating because it is readily dissociated and also be- cause the nitric acid formed by its contact with proteid is itself corro- sive. The only soluble salts which are largely used are the acetates, and these are slowly dissociated and the acid is only slightly active, so that the astringent metallic ion alone comes into play. Symptoms. In ordinary therapeutic doses, the acetate of lead (sugar of lead) has a sweetish, metallic taste followed by a feeling of astringeucy, and induces no symptoms except constipation. The stools after lead are often said to be dark in color from the sulphide formed in the intestine, but this does not seem to be the general rule. Prob- ably little lead is absorbed from an ordinary dose of the acetate ; at any rate no symptoms arise from the general action of the metal ab- sorbed. Lead acetate solutions applied to the skin have no effect, but mucous membranes, or exposed tissues, such as ulcers, are covered with a thin pellicle of albuminate, which serves to protect them from irritation, and thus promotes their healing. When very large quantities of acetate are swallowed, particularly if in a concentrated form, they give rise to the ordinary symptoms of irri- tant poisoning, nausea, vomiting, pain in the abdomen, violent purg- ing or sometimes constipation, blood in the vomited matter and stools, great thirst, weakness, and collapse. In some instances in which the patients recovered from these symptoms, they subsequently suffered from chronic lead poisoning, but apart from these, nothing in the course of acute lead poisoning suggests the absorption of the metal, all the symptoms being obviously due to the local effects on the stomach and bowel, and to the consequent collapse. In fact the effects of a sudden absorption of lead in man are unknown. In animals also, some difficulty has been met in inducing the symptoms due to the action of large quantities of lead in the tissues, because most forms of lead injected into the vessels precipitate the proteids of the blood and cause embolism, while, on the other hand, only local symptoms can be induced by its administration by the mouth. Harnack investigated this LEAD. 671 point by injecting salts of lead-triethyl, in which the metal is not contained in a dissociable form, but which is decomposed in the tissues and then gives rise to lead symptoms. In this way he hoped to be able to elucidate the symptoms of chronic lead poisoning, but his results have not been of much value for this purpose, although they are of some interest. In the frog he found that his compound produced general paralysis, which he ascribed to action on the muscles, but which Wyss later stated to be due to action on the central nervous system. Harnack describes the muscles as being easily fatigued, and gives some further peculiarities induced by lead in them, but Wyss found in apparently equally satisfactory experiments that the muscles were practically unaffected at death. In the dog large doses of lead injected into a vein induced weakness and paralysis, violent diarrhoea, chorea-like movements, tremors, which often assume the appearance of true convulsions, and ataxia. The diarrhoea was attended by severe colic, and both of these symptoms were removed by atropine. It would therefore appear that the colic is here due to nervous influences, and not to the muscle of the intestine being immediately acted upon, for atropine paralyzes only the terminations of nerves. The diarrhoea Harnack found to be due to violent contrac- tions of the intestinal walls, which maintained a certain degree of contraction even when no peristaltic wave was passing. This action of lead upon the intestine is of interest, because it bears a close relation to the colic observed in chronic lead poisoning in man, although here there is generally con- stipation, and also because it connects lead with the other heavy metals, all of which have more or less specific action on the intestine. The ataxia and other brain symptoms also have their counterpart in the brain symptoms of chronic poisoning in man. A single dose of a lead salt does not generally give rise to any symp- toms which would indicate the absorption of the metal, but the con- tinued ingestion of small quantities by way of the stomach, or by inhalation by the lungs, induces chronic poisoning, which can be ex- plained only by its absorption. There seems some reason to believe that lead is absorbed from the unbroken skin, though it is possible that some of the metal was carried to the mouth and swallowed with the food in the cases on which the statement is founded. Lead is appar- ently Absorbed more rapidly than most of the metals except mercury, and remains lodged in the tissues a long time, the excretion taking place only very slowly. It is found in most organs in cases of poison- ing, particularly in the liver and kidney. It is Excreted in the urine, the bile, the secretion of the intestinal epithelium, and in milk and saliva. It is still disputed whether it is eliminated by the skin glands, or whether the lead often seen on the skin in cases of poisoning is not simply deposited there as dust from the air. Chronic Lead Poisoning is the commonest of all forms of metallic poisoning, and at the same time one of the most insidious. It is al- ways accidental, and although it is most common in workers in lead, may occur in persons who are not apparently liable to come in contact with the metal. There is no question that some people are much more susceptible to lead than others. Anemia and weakness from any cause are generally believed to predispose to the disease, women and children are more liable to it than men, and alcoholism and previous lead in- toxication increase the tendency to the attack. Relapses are very common, and may occur years after the first symptoms, even although 672 THE HEAVY METALS. there has been no further exposure in the interval. Lead smelters, workers in white lead factories, painters, plumbers, electricians, and typesetters are liable to lead poisoning from continually handling the metal ; but other trades are not exempt from it, and sometimes the channels by which it gains entrance to the body are very obscure. Some of the more common causes of poisoning are lead water-pipes or cooking utensils, lead used to close tins of meat or fruit, and lead in hair dyes. Formerly a common source of poisoning was wine and cider to which lead had been added to reduce the acidity. A consider- able number of cases of poisoning have been recorded from the use of lead preparations as abortifacients. The symptoms of chronic lead poisoning vary greatly in different cases, sometimes only one or two organs being attacked, in others the whole economy appearing involved in the disorder. The symptoms may be divided into groups for convenience, but it is to be noted that many of these appear to be closely inter-connected, and that in many cases it is impossible to decide whether a set of symptoms is due to direct action upon a single organ, or to the simultaneous disease of several. The Mouth, Stomach and Digestion very often give early indications of lead poisoning. The patient complains of loss of appetite, nausea, constipation, wasting, a metallic taste and foetid breath, and a blue- black line is seen along the margin of the teeth where they enter the gums. This " lead line " is due to the precipitation of lead sulphide by the hydrogen sulphide produced by the action of bacteria, and it is often absent, especially where the teeth are not carious and are kept clean. The metallic taste seems due to the excretion of lead in the saliva, and the loss of appetite may arise from the same cause. These symptoms may be produced in animals also. Virchow and Maier found in one case in man the gastric epithelium in a state of fatty de- generation, and proliferation of the connective tissue of the mucous membrane. Another early symptom is Anaemia, which may be due in part to the malnutrition, but is attributed mainly to an abnormal destruction of the red cells of the blood ; the white corpuscles are increased in many cases but not in all. It is often accompanied by jaundice, with the highly pigmented urine and other symptoms which usually follow the liberation of large quantities of haemoglobin from the breaking up of red cells. It is stated that the red blood-cells often contain granules staining with basophile dyes and indicating incomplete disappearance of the nucleus ; this change may present itself before any other symp- tom. The anaemia is often very marked, and is sometimes the chief or only symptom of lead poisoning ; according to some authorities, it is present in a greater or less degree in the majority of white-lead work- ers, and it leads to weakness, languor, and in young women often to amenorrhoaa. Abortion is very often met with in lead poisoning, and in women employed in lead works who do not show any marked symp- toms of disease. The children of parents suffering from lead are often LEAD. 673 weak and undersized, and a very large proportion of them die in early infancy. One of the commonest symptoms is Lead Colic, painters' colic, colica saturnina or colica Pictonum. This generally sets in suddenly, and is accompanied in most cases by obstinate constipation, in a very small proportion by diarrhoaa. Paroxysms of the most acute agony are fol- lowed by intervals of comparative freedom from pain, but in these in- tervals some tenderness of the abdomen may be complained of, while during the attack pressure generally relieves the pain. The colic lasts for several days, or a week, and then disappears, but is liable to return at intervals. The abdomen is generally hollow, retracted and hard, and during the acute spasms the patient often gains some relief by lying on his face with the fists pressed against the umbilical region, to which the pain is usually referred. Vomiting is frequently present, the pulse is slow and very hard, especially during the acute crises, while the respiration may be accelerated. The urine is scanty, and, according to Stokvis and Nakorai, contains hsematoporphyrin. The cause of lead colic is evidently spasm of the intestine, which is generally attributed to action on the nervous ganglia of the walls. It can be induced in animals, and according to Harnack, is relieved by atropine, which would support the belief that it is of nervous origin. The blood-pressure is raised in man, not only during the spasms, but also in the intervals. This contraction of the vessels and the slowing of the pulse is often said to be reflex from the pain, but this seems to be disproved by the fact that it remains during the intervals. Some writers have therefore regarded the colic and its attendant symptoms as due to a vascular spasm, and have supported this by showing that nitrite of amyl, which dilates the vessels, also relieves the colic. On the whole, the colic appears to be of nervous origin, but whether the focus of disease lies in the wall of the intestine, in the nerves leading to it, or in the central nervous system, it is impossible to de- termine at present. Another common result of chronic lead poisoning is Paralysis, lead or painters' palsy, paralysis saturnina, which is almost invariably limited to certain groups of muscles, the extensors of the forearm. It is bilateral in the great majority of cases, but sometimes involves only one arm. The affection generally begins in the middle and ring fingers, which cannot be extended, then spreads to the index and little finger, and afterwards to the thumb and wrist. The fingers remain flexed and later the wrist is similarly affected, so that the condition is often known as wrist-drop. Even after all the other muscles of the ex- tensor surface of the forearm are involved, the supinator longus remains normal as a general rule. The muscles affected atrophy rapidly, and in old cases contracture of the flexor muscles sets in, when the limb becomes immovable and has a characteristic claw-like appearance. More rarely other regions are affected, such as the laryngeal muscles (in the horse), the external rectus of the eye, or the muscles of the leg. In rabbits and guinea-pigs several observers have succeeded in inducing 43 674 THE HEAVY METALS. paralysis of the hind limbs, and the legs are said to be affected very often in young children. When paralysis is complete, the induced electric current fails to cause contraction, whether it is applied to the muscle or to the nerve, but the galvanic shock induces an abnormally strong contraction when it is passed through the muscle, the make shock having more effect than the break ; the contraction is more pro- longed, the relaxation slower than in normal muscles. This reaction of degeneration is said to occur in the other muscles in lead poisoning, even when no paralysis can be detected in them. The cause of lead palsy is still undecided, for while in some cases there is undoubtedly a peripheral neuritis and nerve degeneration, and no anatomical lesion of the spinal cord, yet in others very distinct degeneration of the cord, particularly of the cells of the anterior horn, has been observed. Al- though the majority of pathologists at the present time are of the opinion that the lesion is a peripheral neuritis, and that the degenera- tion of the cord is either a consequence of this, or is perhaps an en- tirely independent lesion, some authorities hold that the focus of dis- ease is situated in the cord, and that the neuritis is merely an extension of the process. They explain the absence of visible changes of the cord in some cases by supposing that the function of the cell is de- stroyed by the poison, without actual anatomical lesion. A third view which was held formerly, but has been abandoned except by a very few, is that the original lesion is in the muscles. Peripheral neuritis has been elicited repeatedly in animals. Local Anaesthesia is also observed occasionally, though much more rarely than paralysis. It is generally sudden in its onset, but may be preceded by numbness or tickling of the skin, and generally lasts only one or two weeks, when sensation returns again to the part. Lead Arthralgia is more commonly observed, perhaps because it is so much more evident. It consists in sharp lancinating or boring pains in the joints, bones, or the flexor muscles around the joints, the intensity of the pain being comparable only to that of lead colic. It sets in suddenly, usually in the night, and generally disappears as sud- denly. This symptom is not in any way dependent on the gout which is often induced by lead poisoning, and its explanation, like that of the anaesthesia, is quite unknown. Lead Amblyopia, or blindness, is one of the rarer affections. The sight may be lost completely, or may only be dim, and the onset may be sudden or gradual. In some cases the ophthalmoscope gives no clue to the cause of the blindness, in others an acute papillitis is made out. Stood ascribes the amblyopia to several causes, which may each give rise to it separately or may act together. The first of these is a neuritis of the optic nerve in the eye, which gives distinct ophthal- moscopic appearances. In the second the neuritis may be descend- ing or retrobulbar, and may induce little visible change, while the third cause of blindness may be uremia with an effusion into the optic sheath, and a fourth is albuminuric retinitis, these two last forms being due not to a direct action on the nerve, but to the nephritis in- LEAD. 675 duced by the poison. The sudden cases of blindness are probably due to uraemia, and the prognosis in all forms depends on the duration of the neuritis, and, in the case of albuminuria, on the extent to which the kidney is involved. In early cases of neuritis, the disease can gener- ally be arrested and even complete restitution may take place, but if it be neglected, optic atrophy follows. Under saturnine Encephalopathia, a number of disorders of the brain are classed together. They are comparatively rare at the present time, and their onset generally indicates long standing and neglected lead intoxication, although in some cases the patient has been shown to be exposed to the poison for only a short period. An attempt has been made to divide the symptoms of encephalopathia saturnina into four groups, but as the author himself remarks, one of the most character- istic features is the rapidity with which the disease changes from one type to another, and the diversity of the symptoms present at one time. These cerebral symptoms sometimes appear suddenly, while in other cases they are heralded by violent headache, giddiness and sleep- lessness, or by amblyopia, deafness, great depression, stupor, weakness, and tremor. Later, sudden mania and delirium, with convulsions re- sembling chorea or epilepsy, hallucinations and illusions indistinguish- able from those of alcoholic delirium, sudden apoplectic paralysis, ataxia, partial analgesia, hypersesthesia, or coma may occur separately or in succession. Oliver states that the encephalopathic symptoms are especially liable to occur in persons addicted to alcohol. In animals cerebral symptoms are readily induced by lead, either by intravenous injection (Harnack), or by chronic poisoning with the ordinary salts. Chorea, tremors and general convulsions have been caused in this way in dogs. The encephalopathia is obviously of cerebral origin for the most part, although the lower divisions of the central nervous system are also involved in many cases. In several autopsies of patients dying from lead poisoning, atrophy of parts of the cerebrum, or haemorrhages have been found, and very frequently disease of the brain vessels periarteritis, endoarteritis, atheroma or hyaline degeneration has been met with. In other cases of undoubted encephalopathia in man, no such lesions have been observed, and in animals poisoned by Har- nack's method they are certainly not present. Many of the symptoms are obviously not due to these gross lesions, for the suddenness of their onset and of the recovery precludes any such explanation, and show that lead has also a direct action on the brain cells. Lugaro and Schaffer have described some alterations in the chromatin and the dendrites of the nerve cells, which they suppose indicate this direct affection ; McCarthy found marked changes in the capillaries of the cerebral cortex in a dog which was subjected to the action of lead for two months and which presented symptoms of cerebral disorder similar to those met with in chronic poisoning in man. It must be noted that in addition to these generally recognized symp- toms of encephalopathia saturnina, several obscure chronic nervous 676 THE HEAVY METALS. diseases have been ascribed by Putnam and others to lead intoxication, and it is certainly possible that its action may prove to be even more wide-reaching and insidious than is generally recognized at present, but it does not seem profitable to enter upon further details in the present state of the subject. Another organ acted on by lead, especially in prolonged poisoning, is the Kidney, which is often found to present a typical red granular nephritis. During life the urine presents the ordinary appearances of this disease, being copious in amount and of low specific gravity, and containing comparatively small quantities of albumin or casts. In some cases in man, the kidney has presented a mixture of parenchyma- tous and interstitial disease, while in animals the parenchyma alone is affected, perhaps because the experiments have not lasted long enough. The disease of the kidney from lead poisoning, as from other sources, may cause dropsy, uraemia and amblyopia, but it is to be noted that the brain and eye may be affected in cases in which there is no nephritis. Gout is very common in lead poisoning, which evidently predisposes to this disease, if it does not actually cause it, for Garrod states that in one-fourth of the cases of gout treated by him there was a history of lead poisoning. It occurs only after prolonged exposure to the metal, and differs from ordinary gout in the rapidity with which it spreads from one joint to another, as well as in some other features (Luethje). Thus gout is seen without nephritis and vice versa, the two affections being quite independent of each other. The uric acid of the urine is not increased, while that of the blood is said to be abnormally high. In districts where ordinary gout is rare, lead poisoning seldom leads to it, but where ordinary gout is met with, it is a fairly common com- plication of saturninism. Another condition in which lead poisoning may act as a predisposing factor is Arteriosclerosis ; the malnutrition, anaemia, and renal changes induced by the metal would in themselves tend to induce changes in the vessels throughout the body, and degeneration of their walls is met with in a considerable proportion of cases of very prolonged exposure to it. Lead poisoning runs no definite course. As a general rule the anaemia, wasting, constipation and weakness appear early, and then colic may follow, or paralysis, or arthralgia. Nephritis, encephalopa- thia, anesthesia and gout are rarer, and as a rule only occur in very prolonged poisoning. Any one of these symptoms may be present alone, and the diagnosis is then very difficult. In doubtful cases the urine ought to be examined after the administration of iodide, or the stools may be tested for lead. Every case in which lead is found in the urine is not necessarily one of lead intoxication, however, for it has been detected in a number of perfectly healthy individuals. It is impossible at present to give any general explanation for the diversity of the forms of chronic lead poisoning. The central nervous system is certainly acted on, both in its higher and lower divisions, LEAD. 677 but it is still disputed how far the paralysis, arthralgia and anaesthesia are symptoms of central action, and how far they are due to peripheral neuritis. All of the symptoms, however, except those from the mouth, stomach and kidney, and the anaemia and gout seem to be due to affec- tions of either the central or peripheral nervous system. The lead line, metallic taste and nausea, and perhaps the constipation, would seem to be connected with the excretion of the metal along the ali- mentary canal, while the renal action is probably of the same nature as that inducing periarteritis in the brain and, as is alleged, in the lungs under some conditions. The anaemia indicates an action on the red cells of the blood, and the gout some disturbance of the general nutrition. Attempts have been made to elucidate the nature of this action om metabolism by estimating the urea and other constituents of the urine, but no important light has been thrown on it by this means, nor in fact are significant results to be hoped for in a disease which offers so many and so diverse types as lead poisoning. Lead acts upon so many tissues that it might be expected to have some distinctive action upon the simpler organisms, but, as a matter of fact, it seems less poisonous to them than most other heavy metals. PREPARATIONS. PLUMBI ACETAS (U. S. P., B. P.), lead acetate, sugar of lead (Pb(C 2 H 3 O 2 ) 2 -f 3H 2 O), forms colorless crystals, with a sweetish, astringent, afterwards metallic taste, very soluble in water, less so in alcohol. 0.05-0.3 G. (1-5 grs.). Unguentum Plumbi Acetatis (B. P.), 4 per cent. Suppositoria Plumbi Composita (B. P.) ; each contains 3 grs. of lead acetate and 1 gr. of opium. Pilula Plumbi cum Opio (B. P.) contains about 12J per cent, of opium. 2-4 grs. Liquor Plumbi Subacetatis (U. S. P.), Liquor Plumbi Subacetatis Fortis (B. P.), Goulard's extract, an aqueous solution containing about 25 per cent, of lead subacetate (approximately Pb(C 2 H 3 O 2 ) 2 PbO). When exposed to the air, the insoluble lead carbonate is formed. The subacetate solutions are alkaline in reaction. Liquor Plumbi Subacetatis Dilutus (U. S. P., B. P.), lead water, Goulard's lotion or water, a solution containing about 7.5 parts (3 parts B. P.) of the subacetate in 1,000 parts of water. Glycerinum Plumbi Subacetatis (B. P.). Unguentum Glycerini Plumbi Subacetatis (B. P.). --Ceratum Plumbi Acetatis (U. S. P.), Goulard's cerate. Plumbi Carbonas (B. P.), white lead ((PbCO 3 ) 2 Pb(OH) 2 ). Unguentum Plumbi Carbonatis (B. P.). Plumbi lodidum (U. S. P., B. P.) (PbI 2 ). Emplastrum Plumbi lodidi (B. P. ). Unguentum Plumbi lodidi (B. P.). Plumbi Oxidum (U. S. P., B. P.), litharge (PbO). Plumbi JS/itras (U. S. P.) (Pb(NO 3 ) 2 ). Lead plaster or diachylon plaster, Emplastrum Plumbi, is formed from the oxide but is mentioned elsewhere. (See Part VI.) Therapeutic Uses. Lead is used in therapeutics only for its astrin- gent action. The acetate is prescribed internally in diarrhoea, gener- 678 THE HEAVY METALS. ally along with opium, and always in pill form, as the solution would act on the stomach and have less effect on the bowel. It has been tried in dysentery and cholera, but has proved of little value. Lead has also been advised in cases of haemorrhage from the lungs, kidneys and uterus, but is quite valueless here, as it acts as a styptic only when applied locally. Still less reason is there for its use in nephritis, cys- titis and similar conditions. Externally, a* solution of the acetate or the dilute solution of the subacetate is used as an astringent lotion in burns and as an injection in gonorrhoea. White lead has been advised as a dusting powder in burns and skin affections, but is not superior in any way to other similar preparations, and is liable to be absorbed. Nitrate of lead has a reputation in the treatment of onychia. Lead ought not to be employed externally or internally except for a short time as otherwise symptoms of poisoning may arise. Poisoning. In acute lead poisoning, the indications are its removal from the stomach by washing, and its precipitation, which may be best accomplished by solutions of the sulphates such as of magnesium sulphate. In the absence of the sulphates, white of egg or milk is given to form the insoluble albuminate. In chronic poisoning, the general treatment is the removal of the patient from the danger of further poisoning, the administration of iodide of potassium, and nutritious, strengthening diet. The iodide of potassium has been said to accelerate the elimination of lead by the kidneys, but according to Lehmann's experiments is not superior to the bromide or the chloride of potassium, and it has been recently denied that it has any effect on the excretion by the urine or by the intestine, by which most of the lead escapes from the body. In practice, how- ever, the iodide is always used. Diuretics may be prescribed, and hot baths ; sulphur baths are especially recommended, and massage is said to hasten the elimination of the poison. In colic, morphine or opium is often necessary to allay the pain. Belladonna or atropine is used less frequently, and nitrite of amyl is said to be efficient for a short time. In the intervals between the paroxysms, a saline cathartic is often necessary to relieve the constipa- tion, or if the vomiting prevents this, a large enema may be thrown into the bowel. In arthralgia, the pain may necessitate the giving of opiates. In anaesthesia and encephalopathia, the treatment is expectant and symp- tomatic ; for instance, in mania, or violent delirium, chloral may be necessary. In paralysis, strychnine may be used along with the general treat- ment, but the chief reliance is to be placed on the electrical stimula- tion of the paralyzed muscles, first with the galvanic current, and, as recovery sets in, with the induction coil. Massage of the muscles is also of benefit. Nephritis and gout due to lead poisoning are to be treated in the same way as those arising from other causes. LEAD. 679 In lead works and paint factories, much may be done to prevent lead poisoning. Dust is to be avoided as much as possible, and where this is necessarily present, the rooms ought to be thoroughly ventilated. The necessity of frequent bathing and of thorough washing before meals ought to be impressed on the workmen, and no food is to be admitted to the works. A lemonade made with sulphuric acid is often recommended as a prophylactic measure with the object of changing the lead to the insoluble sulphate and thus rendering it less readily absorbed. Poisoning may, however, be induced by lead sulphate, though less often than by the carbonate, which is dissolved by water in the presence of free carbonic acid, and which is changed to the slightly soluble chloride in the stomach. When symptoms of poisoning have appeared, the patient ought not to be allowed to work again, or at least only after a long interval. Weak and anaemic men ought not to be admitted as workmen, and women are not to be employed in lead works more than can be avoided. BIBLIOGRAPHY. Harnack. Arch. f. exp. Path. u. Pharm., ix., p. 152. Wyss. Virchow's Arch., xcii., p. 193. Maier. Ibid., xc., p. 455. Annuschat. Arch. f. exp. Path. u. Pharm., vii., p. 45 ; x., p. 261. Lehmann. Zts. f. physiolog. Chem., vi., p. 528. Mann. Brit. Med. Jour., 1893, i., p. 401. Miura. Berl. klin. Woch., 1890, p. 1005. Oddo et Silbert. Kev. de Med., 1892, p. 295. Gaucher. Ibid., 1881, p. 877. Riegel. Deutsch. Arch. f. klin. Med., xxi., p. 175. Borgen. Ibid., Ivi., p. 248. Ellenberger u. Hofmeister. Arch. f. Thierheilkunde, x., p. 216. Westphal, Archiv f. Psychiatric, xix., p. 620. Stieglitz. Ibid., xxiv., p. 1. Ceni. Ibid., xxix., p. 566. Luethje. Ztschr. f. klin. Med., xxix., p. 266 ; xxxi., p. 112. Stood. Arch. f. Ophthalmol., xxx., iii., p. 215. Kchroeder. Ibid., xxxi., i., p. 229. Cornil et Brault. Journ. de I'Anat., 1883, p. 205. Coen e D' Ajutolo. Ziegler's Beitrage, iii., p. 451. Charcot. Arch, de Physiol., 1881, p. 126. Walton. Boston Med. and Surg. Jour., cxxiii., p. 411. Webber. Ibid. , cxxv. , p. 462. Putnam. Ibid., cxvii., pp. 73, 596 ; cxxviii., p. 187. Ebstein. Virchow's Arch., cxxxiv., p. 541. Eichhorst. Ibid., cxx., p. 217. Lugaro. Centralbl. f. Physiol., 1897, p. 211. Scha/er. Ung. Archiv f. Med., ii., p. 43. Provost et Binet. Kev. Med. de la Suisse Komande, 1889. Lorimer. Brit. Med. Jour., 1886, ii., p. 163. Oliver. Lancet, 1891, ii., p. 530. Lead poisoning, London, 1891. Virchow. Berl. klin. Woch., 1884, p. 75. Trimborn. Centralbl. f. klin. Med., 1891, p. 44. White and Pepper. Trans, of Amer. Assoc. of Physicians, 1901, p. 410. McCarthy. Univ. of Pennsylvania Med. Bull., January, 1902. Billings. Journ. Amer. Med. Ass., 1904, p. 772. 680 THE HEAVY METALS. V. COPPER. Copper seldom gives rise to poisoning, and is much less frequently used in medicine than many of the other heavy metals. The soluble salts precipitate proteids from solution, and are therefore astringent when applied to the mucous membranes and to wounded surfaces. In larger quantities they are somewhat irritant and corrosive, although much less so than mercury. Symptoms. The copper salts have a harsh, metallic, astringent taste, and when swallowed in some quantity cause nausea, salivation and vomiting. The most of the salt is thus removed, and no further symptoms are observed. Large quantities, however, induce corrosion of the walls of the stomach and intestine, and give rise lo violent vom- iting and purging, the copper giving a blue or green color to the vom- ited matter and the stools, and blood appearing in them later from the corrosion of the mucous membrane. Violent pain in the abdomen is complained of, and the usual symptoms of acute corrosive poisoning may follow collapse, with weak pulse and respiration, headache, giddiness, unconsciousness, delirium, coma, convulsions and paralysis. These may prove fatal in a few hours, but more frequently the patient lives for several days to eventually sink from exhaustion. The nausea, vomiting and purging of acute copper poisoning are due to the local effect on the mucous membranes of the stomach and intestine. In fact, although some copper is absorbed in these cases, there is no reason to sup- pose that any of the acute symptoms are due to it, for they are all induced by other poisons which act only as gastro-intestinal irritants. It is still disputed whether chronic copper poisoning occurs in man. The question is of great hygienic interest, because copper is used very often to give color to preserved vegetables, such as peas, is added to flour to improve the bread, and may enter into the food from the use of copper cooking ves- sels, and in a variety of other ways. In copper and brass workers, gastro- intestinal catarrh, or colic and diarrhoea, occur occasionally and are ascribed to the copper swallowed in the course of their occupation. The dust inhaled may similarly cause laryngeal irritation and bronchitis. The skin and hair have often a greenish tint, and a green line on the teeth, just where they enter the gums, is known as the copper line ; but it is believed that these are due largely to the copper dust deposited on the skin, hair and teeth, and not to the excretion of the metal. Local paralysis, anaemia, tremor, emaciation and cutaneous eruptions are said to have followed these symptoms in some cases, and have been held to indicate that copper is poisonous after absorp- tion, but it may fairly be doubted whether these symptoms are really due to the copper or to the lead, arsenic and other poisons often associated with it. It is certain that only a very small proportion of workers suffer from any symptoms whatever, and that the great majority enjoy excellent health. Furthermore, copper has been taken in the form of the metal, or of its soluble salts for prolonged periods without any symptoms being elicited except those of slight intestinal catarrh and some nausea. Animals have been fed with food containing large doses of copper for many months, apparently without any symptoms of poisoning, and copper is found so regularly in the tissues of man and animals that it may be regarded as a normal constituent, although its function is altogether unknown and it may be merely stored up on its way to excretion. Of course it is possible that there exists in certain persons an idiosyncrasy for copper, and that these suffer from the ingestion of quantities which are harmless in others. But until the symptoms have been more def- COPPER. 681 initely determined, and have been shown not to arise from the other poisons associated with copper, it is impossible to consider this form of intoxication as satisfactorily established, and there is no reason to suppose that poisoning can be induced by small quantities of copper such as are contained in pre- served vegetables or in food cooked in copper vessels. In animals the general action may be elicited by the injection of copper into the blood or subcutaneously. The ordinary salts are inadmissible by the former method, as they precipitate the proteids of the blood and cause embolism, and double salts, such as the tartrate of copper and sodium, or proteid compounds, such as the albuminate dissolved by means of alkalies, have therefore been used. A special form of proteid combination has been formed in the same way as artificial ferratin, and is found to act more slowly than ordinary salts. In the frog, copper induces great weakness and event- ually complete paralysis of the spontaneous movements and of the heart. Harnack attributed this to direct action on the muscle, but later observers have found that the central nervous system is primarily affected, and that the muscles retain their irritability after complete paralysis of the spinal cord. There is, however, a direct action on the muscles also, for they lose their irritability very soon after death, and even before the spontaneous move- ments have ceased, the contraction of the muscles on direct stimulation being much weaker than usual. Very often fibrillary contractions are observed early in the frog, but it is unknown whether these are of central or of peri- pheral origin. The heart is somewhat accelerated at first by very small quantities, but later becomes slow and weak, and finally ceases in diastole before the skeletal muscles are paralyzed ; the changes in the heart are due to direct action on the muscle. In mammals the intravenous injection of copper does not cause vomiting, according to most authors, thus proving that the emetic action is due to the irritation of the stomach, and not to any action on the medulla. When large quantities are injected, the locomotion soon becomes slow, clumsy and weak, and later, complete paralysis of the spontaneous movements follows. The heart and respiration seem equally involved, but the respiration ceases somewhat earlier than the heart. The blood-pressure rises slightly after the intravenous injection of copper, but afterwards falls, partly on account of the weakness of the heart, and partly from failure of the vaso-motor nerves to maintain the contraction of the blood vessels. When an animal survives longer, violent, sometimes bloody, diarrhosa is generally induced by copper, as by most of the other heavy metals. The animals lose flesh rapidly, and refuse food, and the urine often contains albumin, and according to some authors, haemoglobin and blood. In the rabbit some icterus and anaemia is said to occur from the destruction of the red blood cells, and fatty degen- eration of the liver, kidney, and heart have been observed. Others have found ecchymoses and congestion along the intestine and in the kidney to be the chief lesions. Similar results are obtained in rabbits when copper is given by the mouth, as this animal is incapable of rejecting the poison by vomiting. In the dog, on the other hand, poisonous doses seem to be re- moved by vomiting when they are given by the mouth ; it is possible, how- ever, that animals may show symptoms of poisoning from the prolonged ad- ministration by the mouth of quantities just too small to cause vomiting. Copper is certainly absorbed from the stomach and intestine, for large quantities have been found in animals fed on it for some time. Baum and Seeliger state that a very large proportion of the poison is absorbed when small doses are given, but the proportion lessens as the dose is increased. It also passes into the blood from other mucous surfaces and from wounds. It is said to have a strong affinity for haemoglobin, and to form with it a compound which Kobert has named 682 THE HEAVY METALS. cuprohsemol, and which is stated to be formed very rapidly when copper is injected into the blood, the metal leaving the serum and attaching itself to the corpuscles at once. The copper absorbed from the intestine and stomach is lodged chiefly in the liver, less in the spleen, kidney and thyroid. It is excreted in the bile, urine and sa- liva, in the intestinal secretions, and in traces in the milk, and is said to pass from the mother to the fetus in utero. Copper is found in small quantities in these organs and secretions in man and in animals that have not been treated with it, but in much larger amount after prolonged administration. Taken by the mouth, it fails to cause gen- eral poisoning, because it is slowly absorbed, and also because what is absorbed is withdrawn from the blood by the liver. Copper is found as a normal constituent of the blood in many of the in- vertebrates, in which it performs the same function as the iron of the haemo- globin in the vertebrates. It has been detected in one of the pigments of birds' feathers, and, as has been stated, is so frequently found in the tissues of mammals, both wild and domesticated, that it may be regarded as a nor- mal constituent. Oysters and other animals take it up in large quantities when they live in water rich in copper, and apparently are not injured by it. Many of the higher plants, notably the grape vine, are said to be remark- ably improved by the sprinkling of copper on their leaves, and this is not only from the destruction of parasites, for vines free from any disease show a more luxuriant foliage, and bear more and larger fruit than other healthy plants, which are not treated with it. On the other hand, copper is a deadly poison to several of the lower plants. Thus traces of copper added to the water in which they live, destroy some of the simpler algse, and Naegeli asserts that one part of copper in one thousand million parts of water is sufficient to kill these plants. The parasites of the grape vine, potato, apple, and other plants are destroyed by spraying the plants with copper, and yeast ceases growing in a 0.02 per cent, solution, while penicillium seems to be almost immune to its action. Locke found that the traces of copper contained in water distilled in copper vessels was sufficient to destroy tubifex (one of the annelid worms) and tadpoles, while Bucholtz states that the development of bacteria is stopped by a solution of copper sulphate under one per cent, in strength. Copper thus seems to have a very power- ful poisonous action on certain living forms and to be harmless to others, and the subject deserves further investigation. It is possible that it may prove to act prejudicially to some human parasites, and it is certainly less dangerous to man than many other remedies used as parasiticides and disin- fectants. PREPARATIONS. Cupri Sulphas (U. S. P., B. P.) (CuSO 4 + 5H 2 O), large, transparent, deep blue crystals, without odor, but with a nauseous, metallic taste, soluble in water, scarcely so in alcohol. Dose, as an astringent, 0.015-0.1 G. (J-2 grs.); as an emetic, 0.3-0.6 G. (5-10 grs.). Therapeutic Uses. Copper sulphate is used internally only as an emetic, and for this purpose ought to be given in about one per cent, solution. It acts promptly, and does not leave so much depression and nausea as other metallic emetics, and for this reason is unsuitable as an expectorant. In phosphorus poisoning it is especially valua- ble, as in addition to causing evacuation of the stomach, the metal is deposited on the particles of phosphorus and prevents their absorption. Externally copper sulphate is used as an astringent injection in ZINC. 683 gonorrhoea, and occasionally as a lotion in ulcers and wounds; for this purpose it is employed in one per cent, solution. The solid crystals are sometimes used to touch exuberant granulations for their astrin- gent and corrosive effect. Small quantities of copper sulphate have recently been used to destroy the algse which grow in reservoirs and often give the water a disagree- able odor and taste. The proportion of copper required for this pur- pose is about one part in a million or sometimes in fifty millions ; this treatment does not render the water deleterious to man, for much larger quantities of copper have been taken constantly without injury. The suggestion has also been made to disinfect water contaminated with typhoid bacilli, and some success has been recorded ; the propor- tion of copper required for this purpose appears to be greater than that necessary to destroy the less resistant algse. The chloride of copper is a much more irritant and antiseptic substance than the sulphate. The albuminate of copper, cupratin, which is formed from the albuminate by heating with alkalies, and cuprohsemol, a combina- tion of copper and haemoglobin, have been suggested recently as non-irritant preparations suitable for internal use, but no condition is known at present in which the general action of copper is of benefit. In cases of Poisoning with copper salts, the stomach generally rejects the metal by vomiting, and no emetic is required. Non-corrosive compounds may be formed by giving milk, egg, or other forms of albumin, tannic acid, magnesia, or ferrocyanide of potassium. Morphine may be required for the pain, ice to stop the vomiting. BIBLIOGRAPHY. HarnacL Arch. f. exp. Path. u. Pharm., iii., p. 44; xvii., p. 145. Klemptner. Ibid., 1895, i., p. 346. Lehmann. Arch. f. Hygiene, xxiv., p. 1 ; xxvii., p.-l ; xxxi., p. 279. Tschirch. Das Kupfer, vom Standpunkte der gericht. Chemie, Toxikologie u. Hy- giene, Stuttgart, 1893. Schwartz. Arch. f. exp. Path. u. Pharm., xxxv., p. 437. Robert. Deutsch. med. Woch., 1895, p. 5. De Moor. Arch, de Pharmacodynamique, i., p. 81. Baum u. Seeliger. Centralbl. f. Physiol., 1896, pp. 714, 752 ; 1897, p. 797 ; 1898, p. 108. Trolldenier. Ibid., 1898, p. 108. Locke. Journ. of Phys., xviii., p. 319. Ringer. Ibid., xxii., p. xiv. Wolf. Ztschr. f. physiolog. Chem., xxvi., p. 442. Murray. British Med. Journ., 1900, i., p. 1334. Lewin. Deutsch. med. Woch., 1900, p. 689. Kurth. Medical Record, 1900, Nov. 10th. Richter. Centralbl. f. Bacteriologie (ii.), vii., p. 417. Moore, Kraemer. Amer. Journ. of Pharmacy, 1904, pp. 553, 574. VI. ZINC. The effects of zinc resemble those of copper so closely that they need only brief mention. Like copper, the soluble salts form insoluble albu- minates and therefore possess an astringent action, or in large quantities act as irritants and corrosives. The sulphate is the soluble salt most commonly used in medicine, but the chloride has frequently given rise 684 THE HEAVY METALS. to corrosive poisoning, and is therefore of greater importance than the chloride of copper. The sulphate is much less irritant and more astringent than the chloride, which is used only as a caustic and dis- infectant. Symptoms. The sulphate of zinc has a harsh, metallic taste, and in small doses causes nausea and vomiting, 'in larger quantities violent vomiting and purging, pain in the abdomen and collapse ; these symptoms are due to the local action on the stomach and intestine. The insoluble zinc oxide and carbonate are less liable to cause acute irritation than the sulphate, but their prolonged ingestion has given rise to dyspepsia and constipation or diarrhoea in some cases. The continued administration of zinc salts has no effects in man, except those of disordered digestion and constipation, and Lehmann could detect no effects in the dog, after the administration of 155 G. of the carbonate in the course of 335 days, although a considerable amount of the metal had been absorbed. In workers in zinc, a curious condition known as brassfounders' ague, is occasionally met with. It is ushered in by a sense of general discomfort and weakness, with more or less pain in different parts of the body ; later prolonged rigors and shivering are followed by a rapid acceleration of the pulse, coughing and soreness of the chest, and head- ache. These symptoms give place to profuse perspiration, and the patient sinks into a sleep from which he awakes in ordinary health. The attacks may return frequently, and seem to be due to the fumes of zinc which escape in the process of casting. A number of obscure nervous conditions have also been described as arising from zinc in workmen in brass factories and bronze works, but they seem to be ex- tremely rare, and it is questionable whether they are really due to the zinc or to its impurities, such as arsenic and lead. Action. The general action of zinc can therefore be observed only when it is injected intravenously, or hypodermically. For this purpose, the double salts alone can be used, as the ordinary salts precipitate the proteids of the blood when injected into a vein, and cause acute irritation when ap- plied subcutaneously. In the frog, zinc is found to cause weakness and lessened reflex excitability, and the heart becomes weak and inefficient, ir- regular and slow, and eventually ceases in diastole. The action seems to be exercised chiefly on the central nervous system and the heart, although the voluntary muscles respond more weakly to the electric current in life, and lose their irritability entirely soon after death. Meihuizen inferred from his experiments that the zinc salts reduce the reflex irritability markedly in the frog, but he used an irritant salt and this invalidates his results. In mammals the intravenous injection of zinc causes vomiting and diar- rhoea, weakness, tremor, and paralysis of the extremities ; and the stomach, intestine and heart contain small haemorrhages. The blood-pressure seems to be but little affected, until just before death, but the pulse is slowed. Helpup found that the subcutaneous injection of zinc salts induced conges- tion and parenchymatous inflammation of the kidney. Zinc seems therefore to depress the central nervous system, and to a less extent the heart and voluntary muscles, and to cause irritation and conges- tion of the mucous membrane of the stomach and intestine, and inflamma- tion of the kidney. The fact that vomiting occurs from the intravenous in- jection of zinc salts might seem to indicate that it acts directly on the ZINC. 685 medullary centre for vomiting, but may more probably be explained by the metal inducing inflammation in the stomach. These effects occur, how- ever, only when the metal is administered by way of the blood vessels or subcutaneously. Zinc has, according to Grahe and Robert, a special affinity for the hemo- globin, with which it forms a compound (zinc-haemol), but its administration has no effect on the formation of haemoglobin. Lehmanu found that of the zinc absorbed from the stomach and intestine, most is contained in the liver and bile, less in the spleen, kidney, thyroid and pancreas, and very little in the other tissues. Zinc is excreted by the stom- ach and intestinal walls, and in much smaller amounts in the bile and urine. Locke found zinc to possess a poisonous action on the tadpole and tubifex when present in traces in the water in which they lived, but this effect was weaker than that of copper. Eichter states that zinc is less poisonous to fungi than copper, and very weak solutions seem to promote their growth. The zinc salts seem to be in general much weaker than those of copper, which they resemble closely in other respects. PREPARATIONS. Zincum (U. S. P.), metallic zinc, is used only to form the other prepara- tions and as a reagent. ZINCI SULPHAS (U. S. P., B. P.) (ZnSO 4 + 7H 2 O), colorless, transparent, odorless crystals, with a harsh, astringent, metallic taste, soluble in water, not in alcohol. 0.5-2 G. (8-30 grs.), as emetic ; 0.05-0.2 G. (1-3 grs.), in epilepsy. Zinci Oxidum (U. S. P., B. P.) (ZnO), an amorphous white powder with- out odor or taste, insoluble in water. 0.1-0.5 G. (2-8 grs.). Zinci Carbonas Prsscipitatus (U. S. P.), Zinci Carbonas (B. P.), a prepara- tion varying somewhat in composition, but always containing some oxide, which it resembles in appearance and solubility. 0.1-0.5 G. (2-8 grs.). UNGUENTUM ZINCI OXIDI (U. S. P.), 1 part to 4 of benzoinated lard. UNGUENTUM ZINCI (B. P.), 15 per cent, of the oxide. Zinci Stearas (U. S. P.). Unguentum Zinci Stearatis (U. S. P. ), 50 per cent. Unguentum Zinci Oleatis (B. P.). Zinci Chloridum (U. S. P., B. P.) (ZnCl 2 ), a white powder, or porcelain-like mass, irregular, or moulded into pencils, odorless and strongly caustic, very deliquescent, and soluble in water and alcohol. Liquor Zinci Chloridi (U. S. P., B. P.), about 36 per cent. Zinci Acetas (U S P B. P.) (Zn(C,H,O f ), + 2H 9 O). 0.05-0.1 G. (1-2 grs.). Zmci Valeras (U S. P., B. P.) (Zn(C 5 H 9 O 2 ) 2 + 2H.O). 0.05-0. 1 G. Zinci Bromidum (U. S. P.) (ZnBr 2 ). 0.05-0.1 G. Zinci lodidum (U. S. P.) (ZnI 2 ). 0.05-0.1 G. Zmcitiulphocarbolas (B. P.), Zinci Phenolsulphonas (U. S. P.) (Zn(C H SO ) -f 8H O), colorless crystals with an astringent taste, soluble in water and in Used externally in 1 per cent, solution. (See page 422.) Therapeutic Uses. Zinc sulphate has been used internally as an emetic, but not so widely as the sulphate of copper, although it is equally efficient. The sulphate, the oxide and the carbonate have been advised in the treatment of various brain diseases, such as epilepsy chorea and hysteria, in which zinc is believed to act as a sedative' Jixpenments on animals and on healthy persons give no reason to be- lieve in this sedative action, and clinicians are divided as to its useful- ness m these diseases, but there is some support for the treatment The oxide and sulphate are seldom employed as astringents in diarrhoea Externally, the zinc preparations, with the exception of the chloride 686 THE HEAVY METALS. are used as astringents, the sulphate being applied in solution, the oxide and carbonate as powders or as ointments, which most prefer to the oleate. The oxide is especially useful as an application in many skin diseases. Solutions of the sulphate are used as an eye wash (J per cent.) and as an injection in gonorrhoea (1-4 per cent.). In the last case it is sometimes formed into a mixture with acetate of lead, the sulphate of lead which results being credited with some astringent action and not being washed off so readily from the diseased surface. The sulpho-car- bolate is also used as a urethral injection, and the salicylate and the sulpho-iodolate of zinc have also been introduced as astringent and anti- septic applications. The chloride of zinc differs from the other salts in being a powerful caus- tic, and is used as a paste or in pencil form to destroy malignant growths, or in chancres and gangrenous sores. It produces a white eschar and is said to be less liable to spread over the surface than potash, but penetrates the epi- dermis with difficulty, and it is therefore advisable to destroy this with pot- ash or a blister before applying the caustic. It is sometimes mixed with flour or dried gypsum and water to a paste (Canquoin's paste), when a less active caustic is desired. Its use is much more restricted at the present time than formerly, when there was greater apprehension of the minor surgi- cal operations, but it has been recommended as a caustic and disinfectant application in inoperable cancer. In very dilute solution it has been applied as a disinfectant lotion or injection (1 in 5,000). Burnett's disinfecting solu- tion (a somewhat stronger solution than the official liquor) is used to disin- fect faeces and urinals, and the liquor of the pharmacopceia may be employed for the same purpose. It has frequently given rise to severe corrosive poisoning from being swallowed accidentally or suicidally. The acetate of zinc acts in the same way as the sulphate and may be used for the same purpose. The valerianate and bromide have been introduced with the intention of combining the action of zinc with that of valerian or bromide in hysteria and epilepsy, but valerianic acid is entirely devoid of any action on the brain (see Valerian, page 74) and the bromide is given in too small doses to exert any influence. The iodide is used in a similar at- tempt to combine the astringent effects of zinc and the specific action of iodides, but is open to the same objection. The action of the phosphide is practically identical with that of phosphorus. Poisoning with zinc is treated in the same way as that with copper. BIBLIOGRAPHY. Harnack Arch. f. exp. Path. u. Pharm., iii., p. 53. Bucholtz. Ibid., iv., p. 64. Helpup. Inaug. Diss., Greifswald, 1889. Deutsch. med. Woch., 1889, p. 782. Sacher. Arbeit, a. d. pharmak. Instit. zu Dorpat, ix., p. 88. Grahe. Ibid., ix., p. 155. Lehmann. Arch. f. Hygiene, xxviii., p. 291. Morner. Ibid., xxxiii., p. 160. Jacobj. Arb. a. d. k. Gesundheitsamte, xv., p. 204. Volcker. Beitrage z. klin. Chirurg., xxvii., p. 592. Eichter. Centralbl. f. Bacteriologie (II.), vii., p. 417. VII. SILVER. The only salt of silver used at all extensively in medicine is the nitrate, which is caustic, astringent and antiseptic. Added to solutions of proteids, it forms a heavy precipitate of albuminate, which is at SILVER. 687 first white in color but turns darker in the light as the silver is re- duced, and which is soluble in the presence of chlorides. Symptoms. In dilute solution silver is a slight irritant to the skin, and causes redness and itching only, but more concentrated solutions blister, and the solid nitrate of silver causes an eschar, which is at first white, but later turns black from the reduction of the silver in light. On the mucous membrane, dilute solutions act as astringents, but con- centrated cause irritation and corrosion. The caustic action of silver does not extend so deeply as that of some other metals, such as mer- cury, because the penetration of the metal is limited by the membrane of silver albuminate formed. On the other hand, the silver salts are more irritant than those of lead. Dilute solutions of silver nitrate are said to contract the vessels when they are applied locally, and this may be correct under some circumstances, but if irritation is induced, the vessels are certainly dilated. The astringent action is to be attributed not to any action on the vessels, but to the formation of a protective layer of coagulated albumin. In acute silver poisoning from the ingestion of silver nitrate, the symptoms are those of severe gastro-intestinal irritation and corrosion. Burning pain is felt in the throat and stomach, and is followed by nausea and vomiting and often by purging. The mouth is covered with a grayish-white membrane, which turns darker after a time, but this is absent if the poison be swallowed in the solid form, as has hap- pened sometimes. The corrosion of the stomach and intestine causes collapse, with weak pulse, shallow respiration and pinched features, and this may be followed by coma, convulsions and death. The throat, stomach and intestine presented the ordinary appearances of acute cor- rosive poisoning in one case in which an autopsy was performed. Action. The symptoms of acute poisoning are due to the local action, and present no features suggesting that silver is absorbed and causes general poisoning. The action of silver after absorption has, however, been investi- gated in animals poisoned by subcutaneous or intravenous injection. The nitrate, owing to its coagulating properties, is unsuitable for this purpose, and the hyposulphite of sodium and silver, or a solution of the albuminate has therefore been used. In mammals the central nervous system is the chief seat of action, especially the medulla oblongata, which seems to be stimulated at first, for the blood-pressure rises and the pulse is somewhat slow, owing to increased activity of the vaso-motor and vagus centres. Later the blood-pressure falls, and the respiration becomes slow and labored, and eventually ceases from paralysis of the centre. Gaethgens asserts that the diaphragm, and eventually the other striated muscles are paralyzed soon afterwards. The heart is comparatively little affected, and often continues to beat some time after the respiration has stopped. In less acute poison- ing, when the animal survives the injection for several hours or days, a marked increase in the bronchial secretion, culminating in oedema of the lungs, has been noted ; no satisfactory explanation of this has been advanced, but it does not seem due to cardiac inefficiency and occurs also when the excised lung is perfused with blood containing silver. Congestion and ecchymoses are found in the stomach and intestine, and some authors men- tion ulceration of these mucous membranes. Cohnstein found that small 688 THE HEAVY METALS. quantities of silver salts injected intravenously cause some increase in the urine for a time, but that larger quantities are followed by albuminuria. In cold-blooded animals and in invertebrates, silver preparations are said to cause violent convulsions, resembling those of strychnine and followed by general paralysis. The heart is, according to one investigator, little affected, according to another, it is found in diastole. The general action of silver is thus apparently directed first of all against the medulla oblongata, the rest of the central nervous system being affected to a less extent. The mucous membrane of the stomach and intestine is acted on, as by most heavy metals, and the kidney is also liable to irritation. (Edema of the lungs occurs frequently. Chronic Poisoning. There is no evidence that in acute poisoning in man any considerable amount of the metal is absorbed from the stomach and intestine. When silver is given for prolonged periods, however, some is absorbed, although probably only a minute fraction of that actually swallowed. In the stomach small quantities of soluble silver salts are probably changed to the chloride and albuminate, but the form in which the metal is absorbed has proved a subject of dispute. It seems to be taken up in solution, for none of it is found in the epithelium of the stomach and intestine, and some of it may circulate in the blood in a soluble form for a short time. But the greater proportion is very soon thrown down in the form of minute granules, which were for- merly believed to be metallic silver, but which have more recently been said to be one of its organic compounds. The formation of this pigment is quite different from the reduction of silver in sunlight, for it occurs in complete darkness. The change apparently takes place in the cells, especially in the leucocytes, but the granules are afterwards extruded into the surrounding fluid. They are found in the connective tissues of the body chiefly, and when present in quantity, give a dark color to the skin and mucous membranes. This pigmentation (Ar- gyria) was much commoner formerly than at the present time, but several cases have been described quite recently. The chief source of chronic silver poisoning or argyria was formerly the treatment of epilepsy with the nitrate. More recently it has occurred in the makers of artificial pearls, who use silver as a pigment. Local argyria is sometimes met with from the prolonged application of silver nitrate to the eye or throat, when it tints the eyelids and mouth, and from working with silver, when the hands are permanently blackened from the granules being forced into the skin. The deposit of the silver in the skin gives it a darker color, varying from light gray in mild cases to a darker slate shade after more pro- longed use. It is generally distributed all over the body, but in some cases has been especially marked in the face, and it is said to begin in the gums, where it causes a dark, slate-colored line somewhat resem- bling the lead line. In the skin it is found in the corium, not in the epidermis. The deposit and the dark color extend throughout the alimentary canal and the respiratory passages, the granules occurring in the connective tissue, particularly in the intestinal villi, and not in the epithelium. The glomeruli of the kidneys, the connective tissue of the liver and spleen, the choroid plexus, the tunica intima of the SILVER. 689 aorta, the serous membranes, and the mesenteric lymph glands contain more of the deposit than other organs. The pigmentation is not ac- companied by any other symptom of importance, and the victims live to old age without suffering from the chronic poisoning in any way, except from the annoyance induced by the change in color. Argyria is quite incurable, although many attempts have been made to remove it. Iodide has been tried, for the most part without effect, and blistering is equally valueless as the pigment lies deeper than the epidermis. The only known solvent of the granules is cyanide of potassium, and of course this is inadmissible owing to its powerful poisonous action. Argyria has been induced in animals by prolonged treatment with small doses of silver salts, though the pigment is not found in the skin in them, but in the duodenal mucous membrane and the mesentery attached to it, the mesenteric lympii glands, the spleen and liver. A still more limited area of argyria has been caused in animals recently by administering for a few weeks the glycyrrhizinate of silver. It is not unlikely that more prolonged administration would lead to other organs and perhaps the skin being involved. A deposit of silver pig- ment has also been induced in animals by a single injection of a non- irritant preparation into a vein, or into the subcutaneous tissue. Here the silver is found at first in the liver capillaries, the glomeruli of the kidney, the intestine and the bone marrow, but is afterwards taken up by the leucocytes, and carried to all the organs of the body. Various symptoms of chronic poisoning quite apart from argyria have been de- scribed in animals from prolonged treatment with silver, but it would seem that they were due not to the direct action of the drug, but to the continued irritation of the stomach and intestine, as they were entirely absent when less irritant preparations and greater care in administra- tion were used. In man it seems likely that most of the silver passes through the alimentary canal unabsorbed, and that the small proportion taken up by the tissues is precipitated and remains embedded in them indefi- nitely, for the pigmentation remains unchanging in its depth, and there is therefore no reason to suppose that any of the silver is eliminated. In animals, however, some of the silver injected hypodermically or intravenously is excreted by the epithelium of the alimentary canal. None appears in the urine. In the frog, silver injected hypodermically is all excreted by the epithelium of the tongue, is swallowed, and passes out in the faeces. No other poison is known to be eliminated by this channel. Silver nitrate is a powerful antiseptic, partly from its action in co- agulating the proteids of the micro-organisms, partly from the specific effects of the metal, as is shown by the fact that the albuminate of sil- ver is also an active disinfectant. 44 690 THE HEAVY METALS. PREPARATIONS. Ar genii Nitras (U. S. P., B. P.) (AgNO ? ), colorless crystals which be- come gray or grayish-black on exposure to light in the presence of organic matter, with a bitter, caustic, strongly metallic taste, very soluble in water, less so in alcohol. 0.01-0.03 G. (- gr.) in pills made up with kaolin. ARGENTI NITRAS Fusus (U. S. P.), moulded nitrate of silver, lunar caus- tic a white, hard solid, generally cast in the form of pencils. ARGENTI NITRAS INDURATTJS (B. P.), toughened caustic, a silver nitrate fused with 5 per cent, of nitrate of potassium. Ar genii Nitras Mitigatus (B. P., U. S. P.), mitigated caustic, consists of one part of nitrate of silver and two parts of nitrate of potassium fused into rods like lunar caustic. Argenti Ozidum.(U. S. P., B. P.) (Ag 2 O), a heavy, brownish-black powder, odorless and having a metallic taste, very little soluble in water. 0.03-0.1 G. (i-2 grs.). The silver preparations ought to be kept in dark amber-colored bottles, in order to prevent their being reduced by light, and ought not to be prescribed with organic matter, which rapidly reduces them. Therapeutic Uses. Silver nitrate pills have been recommended in some forms of dyspepsia and vomiting, and in gastric ulcer, and have also been used as astringents in diarrhoea, but generally with little benefit. A very ancient use of silver oxide, and more recently of the nitrate, is that in the treatment of epilepsy, chorea, tabes and various other nervous diseases. This dates from the Arabs, and is said to have originated from the astrological medicine of that period, which taught that nervous diseases were especially affected by the phases of the moon, which was associated with silver in their system (hence, lunar caustic, lunacy). Clinical experience shows that silver is of no benefit in epilepsy, and, in fact, it is improbable that silver reaches the central nervous system in any other form than inert granules. This use of silver very often gave rise to argyria without benefiting the pa- tient, about 1530 G. proving sufficient to cause marked pigmentation. Externally, silver nitrate is employed very extensively, the sticks of lunar caustic being used to destroy warts and other small skin growths, to arrest capillary haemorrhage, to destroy the false membranes of diphtheria, and for other similar purposes. Where a milder caustic is required the mitigated caustic is used instead of ordinary lunar caus- tic. A solution of 2-5 per cent, may also be applied to cauterize chan- cres and indolent ulcers, and one of 1-2 per cent, may be painted on mucous membranes as an irritant antiseptic. A solution of common salt is then used to wash the part, in order to remove the excess of silver. In ophthalmia, especially of the infectious form, a solution of 12 per cent, is extremely valuable, and, in fact, a routine treatment in some lying-in hospitals is to wash the eyes of the infant with this solution immediately after birth as a prophylactic measure to prevent oph- thalmia. A solution of this strength is only to be used by the surgeon himself, and the eye should be washed out with a salt solution at once. A more dilute solution (J-J per cent.) may be used as a lotion for the eye more frequently, may be applied to extensive denuded surfaces, as burns, and is often thrown into the rectum in chronic SILVER. 691 dysentery. In gonorrhoea the nitrate of silver, one part in 500-2000 of water, is used as an injection, and is found to have great value, de- stroying the gonococci and promoting healing. Very much stronger solutions (up to 5 per cent.) have been used to abort the disease in its onset, but cause great pain. The precipitation of silver nitrate by proteids and chlorides confines its disinfectant action to narrower limits than those of some other antiseptics, and this has led to the introduction of a number of other compounds, which are less easily dissociated and accordingly less liable to be thrown out of so- lution. Thus argentamine, a ten per cent, solution of silver phosphate in ten per cent, ethylendiamine solution, has been used in gonorrhoea diluted to 1 : 1,000-5,000, in the eye in five per cent, solution. It penetrates better than silver nitrate, but the alkaline diamine renders it somewhat irritating. Another recent product is argonin, which is a combination of casein and silver, is soluble in water, and, like argentamine, is not precipitated by chlorides nor by albumin ; it is a somewhat weaker antiseptic than the nitrate and argentamiue. The lactate of silver, actol, and the citrate, itrol, have also been used as antiseptics. Actol is soluble in water, and resembles the nitrate in coagulating proteids, while itrol, on the other hand, is practically insoluble (1 to 3,800 water). The former is used in solution (i per cent.), the latter as a disinfecting powder in wounds. Actol and argonin have been shown to have very considerable disinfectant power in test-tube cultures, and actol lessens the putrefaction in the bowel and constipates to some extent, but argonin has no effect on the intestinal microbes. Protargol, largin, and many other compounds of silver have been introduced, but all of these have been replaced in the last few years by Crede' s colloid silver ( Collar gol), which is metallic silver in colloid form, which may be suspended in water (4 per cent. ) or in oint- ment (10-15 per cent.). It is said to be efficient as a disinfectant in the same conditions as have hitherto been treated with the nitrate and to be practically devoid of the irritant and corrosive action of the latter. Attempts have been made to use it by hypodermic or intravenous injection in general septicaemia, but the earlier claims of its advocates that it was of value as an antiseptic in consti- tutional diseases have proved to have no more foundation than the similar state- ments in regard to other antiseptics. (See pages 393-396.) Silver preparations ought not to be used for long periods, as argyria has been induced in three months and after the use of 15-30 G. (J-l oz.) of the nitrate. In cases of poisoning with silver nitrate, eggs, milk and, above all, com- mon salt solution are indicated to form insoluble compounds. In argyria no improvement can be expected, though the iodide of potassium may be tried. BIBLIOGRAPHY. Bogoslowsky. Virchow's Arch., xlvi., p. 409. Jacobi. Arch. f. exp. Path. u. Pharm., viiL, p. 198. Rozsahegzi. Ibid., ix., p. 289. Cohnstein. Ibid., xxx., p. 129. Loew. Pfliiger's Arch., xxxiv., pp. 596, 602. Schubert. Zts. f. Heilkunde, xvi., p. 341. Samqjloff. Arb. a. d. pharm. Instit. Dorpat, ix., p. 27. Gerschun. Ibid., x., p. 154. Tschisch. Virchow's Arch., c., p. 147. Crete. Arch. f. klin. Chirurg., lv., p. 861. Mosse. Zts. f. phys. Chem., xxiii., p. 160. Liebrecht. Therap. Monatsheft, 1895, p. 306. Van der Does. Zts. f. phys. Chem., xxiv., p. 351. Athanasiu. Journ. de Physiol., iii., p. 163. Bid. Ztschr. f. physikal. Chem., xl., p. 513. 692 THE HEAVY METALS. VIII. BISMUTH. The insoluble salts of bismuth, in especial the subnitrate, have long enjoyed a reputation in the treatment of gastric and intestinal irrita- tion, and have more recently been advised in surgery as applications to granulating wounds. Symptoms. Taken in therapeutic doses, the subnitrate induces no marked symptoms, even after prolonged use. It has little or no taste, and passes through the stomach and intestine for the most part unab- sorbed. It is said to increase the peristalsis of the stomach and the secretion of mucus, but it may be questioned whether it has more effect here than any other heavy powder. In the intestine it is said to have some effect in increasing the leucocytes of the blood, and often causes some constipation. It gives the stools a black color, which is gener- ally believed to be due to the formation of the sulphide of bismuth, but which Quincke ascribes to the reduction of the subnitrate in the intestine. Very little of the bismuth swallowed is absorbed, but several au- thorities have found traces in the urine of patients treated with it in- ternally so that some evidently passes into the blood under certain unknown conditions. Enormous quantities have been administered internally without any symptoms of poisoning being elicited, but in one or two cases some stomatitis has been remarked, while in other in- stances large concretions of bismuth have been found in the stomach and bowel. Some of the older writers describe serious poisoning from bismuth, but this was not due to the drug itself, but to the lead, arsenic, or antimony with which it was contaminated. 1 As long as bismuth was given only internally, no serious symptoms arose from its action, and in fact any effects whatever beyond slight constipation were ex- tremely rare. But since its use was extended to wounded surfaces, several cases of serious intoxication have occurred. The symptoms are salivation, swelling of the gums, tongue, and throat, pain and difficulty in swallowing, black spots in the mouth and throat, and gan- grene of the soft palate and other parts of the mucous membrane of the mouth. Vomiting, diarrhoea and albuminuria follow, but the pa- tients generally recover when the dressing is removed from the wound. In these cases much less bismuth is applied than is often prescribed for internal use, so that it would appear that it is absorbed more rapidly from granulating surfaces than from the mucous mem- branes, or that what is absorbed from the stomach and intestine is prevented by the liver from reaching the general circulation. Action. The general action of bismuth has been studied in animals by the subcutaneous or intravenous injection of the double salts, such as the tartrate of bismuth and sodium. In frogs the symptoms are those of stimulation of the 1 A symptom formerly noted in cases treated with bismuth was an extremely dis- agreeable odor in the breath, but this has been shown to be due to the presence of tellurium in the preparation. BISMUTH. 693 spinal cord and medulla oblongata, followed by depression and paralysis. The stimulation induces tonic convulsions, which are separated by periods in which the frog is at first apparently normal, but in which symptoms of depression and paralysis appear later. The peripheral nerves and muscles and the heart are little affected. In mammals also, large doses act chiefly on the central nervous system. The respiration is accelerated, the heart slowed, and violent clonic and tonic convul- sions follow at short intervals, during which the movements are weak and inco- ordinated. Toward the fatal issue of the injection the heart often ceases entirely for some time, and then regains its former rhythm quite suddenly. The blood- pressure falls, partly owing to the weakness of the heart, partly from depression of the vaso-motor centre. In some animals the respiration ceases before the heart ; in others, the sequence is reversed. The heart seems to be affected directly, for division or paralysis of the vagus nerves does not alter the effects. Smaller quantities injected intravenously or subcutaneously into mammals induce a more chronic form of intoxication, which resembles that seen in man. The earliest symptoms are loss of appetite, vomiting and diarrhoea, salivation and stomatitis with ulceration of the gums, tongue, and buccal mucous mem- brane. Weakness, slowness and incoordination of the movements follow, and except in very few chronic cases, tetanic convulsions occur at intervals. The urine contains albumin and casts. The weakness gradually deepens into com- plete paralysis and the animal dies, generally without convulsions. The heart seems little affected in the chronic intoxication, but the blood-pressure is low from the intestinal irritation and general collapse. Besides the stomatitis and ulceration of the mouth, the post-mortem appear- ances in chronic bismuth poisoning in animals consist in some congestion, inflam- mation and necrosis in the kidney, and an intense black coloration of the caecum and the upper part of the large intestine. This pigmentation is limited very exactly by the ileocsecal valve, and extends throughout the thickness of the bowel wall. The mucous membrane may also be necrosed in places, and ulcers and haemorrhages are met with in it. The black coloration is due to a deposit of bismuth sulphide on the mucous membrane, and in the capillary vessels and lymph spaces. Meyer and Steinfeld found that bismuth is excreted all along the alimentary canal, but in larger quantities in the caecum and large intestine than elsewhere, and they ascribe the ulceration to the precipitation of the sulphide in the vessels and the consequent arrest of the blood current. When sulphide solu- tion was artificially introduced into the stomach and small intestine, bismuth caused necrosis and ulceration here also, so that there is considerable support for this view. They found bismuth to be stored in considerable quantity in the liver, and to be excreted by the urine, stomach and intestine, but especially by the caecum and large bowel. It has been found in the saliva by other observers, and perhaps in traces in the milk, although the last is not satisfactorily established. The action of bismuth in acute poisoning in animal experiments seems there- fore to be exerted on the medulla and spinal cord, to a less extent on the heart, while in chronic intoxication the organs affected are those by which it is excreted the mouth, kidney, large intestine, and caecum. PKEPAKATIONS. BISMUTHI SUBNITRAS (U. S. P., B. P.), white bismuth, Magisterium Bis- muthi, bismuth oxynitrate, a heavy white powder odorless and almost taste- less, insoluble in water or alcohol but soluble in nitric or hydrochloric acid. It consists of a mixture of the hydrate and subnitrate of bismuth in varying proportions. 1 0.3-2 G. (5-30 grs.), in powder or suspended in water. 1 The B. P. defines this preparation as bismuthoxynitrate (BiONO 3 H 2 O), but some hydrate is almost invariably present. 694 THE HEAVY METALS. BismutU Subcarbonas (U. S. P.), Bismuthi Carbonas (B. P.), bismuth oxy- carbonate, a white or pale yellowish -white powder, varying in composition, odorless, tasteless, insoluble in water or alcohol. 0.3-2 G. (5-30 grs.) in powder. Trochiscus Bismuthi Compositus (B. P.) ; each contains 2 grs. of bismuth oxycarbonate along with the carbonates of magnesia and of lime. Bismuthi Salicy'las (B. P.), Bismuthi Subsalicylas (U. S. P.), the salicylate or oxysalicylate of bismuth, is a white, amorphous powder, insoluble in water. 5-20 grs. Bismuthi Oxidum (B. P.) (Bi 2 O 3 ), a slightly brownish-yellow powder, in- soluble in water. 5-20 grs. Bismuthi Citras (U. S. P.) (BiC 6 H 5 O 7 ), a white powder, odorless, tasteless, insoluble in water or alcohol, used only to form Bismuthi et Ammonii Citras (U. S. P.), small, shining, translucent scales, odorless, but with a slightly acidulous and metallic taste, and becoming opaque on exposure to the air, very soluble in water, less so in alcohol. 0.1- 0.3 G. (2-5 grs.). Liquor Bismuthi et Ammonii Citratis (B. P.) contains the equivalent of 5 per cent, of bismuth oxide. -1 fl. dr. Bismuthi Subgallas (U. S. P.), 0.25 G. (4 grs.), forms a white or nearly white powder, insoluble in water, tasteless and odorless. Therapeutic Uses. Bismuth has been used chiefly in gastric catarrh and ulcer, and has often been looked upon as a specific in the last affection, though it acts simply as a protective powder with perhaps some astringent properties. It has been found that when swallowed it is at first deposited in the most dependent part of the stomach, but is later distributed evenly over the surface, and forms a continuous sheet over any ulceration, which it thus protects from mechanical injury from the food, and also from the chemical action of the gastric juice. The subnitrate is the only one of the official preparations largely used for this purpose, and is generally administered in quantities of 2-3 G. (30-45 grs.) per day in powder. Recently the use of much larger quantities (10-15 G., 150250 grs., per day) has been recommended. Bismuth has also been used in diarrhoaa for its astringent and protective action on the intestine, which is again due to its being deposited on the mucous membrane and acting as a mechanical coating over irritated surfaces. The subnitrate has been advised in surgery as an antiseptic, astrin- gent powder to replace iodoform. It is true that it is devoid of the disagreeable odor of the latter, but it is not a harmless remedy, as was at first supposed, for several cases of bismuth poisoning have been recorded from its surgical use. Like iodoform, its value depends not so much on its germicidal action as on its absorption of the fluids of the wound, which renders the surface less suitable for the growth of bacteria. The therapeutic uses of the bismuth preparations then are largely due to their insolubility. The subnitrate is generally used, the carbonate less frequently, while the soluble double citrate is quite superfluous. Several new compounds of bismuth have been introduced into therapeutics of late years, chiefly with the intention of combining the astringent prop- erties of bismuth with the antiseptic action of benzol preparations. Among ALUMINIUM AND ALUM. 695 these may be mentioned the salicylate (B. P.) and benzoate, which have been used as intestinal antiseptics and astringents. (0.2-0.3 G. (3-5 grs. ), in powder.) Others are dermatol (gallate of bismuth, C 6 H 2 (OH) 3 COOBiO), airol (bismuth oxyiodide gallate), thioform (bismuth dithio-salicylate), bismuth phenolate, cresolate, orphol (/3-naphtolate), xeroform (tribromphenolate), tan- nate, sulphocarbolate, dermol (chrysophenate), eudoxin (tetraiodo-phenolphtalei- nate). These have been used chiefly as cutaneous applications in various forms of skin disease, in which an astringent and protective powder is indi- cated, in burns and ulcers, in some ophthalmic conditions, and as dusting powders after operations. Several of them, such as dermatol (0.1-0.2 G.), and the phenolate, cresolate, naphtolate, and tribromphenolate (1-4 G.), have been advised as intestinal antiseptics and astringents, and the last four have been shown to be decomposed in the intestine into bismuth and the corresponding aromatic antiseptic. Stomatitis and other symptoms have been observed occasionally from the external application of these new com- pounds, but they seem less dangerous than the subnitrate in ordinary sur- gical use. Ttye phenol, cresol, and other similar substances freed by the decomposition of these new compounds, might also give rise to symptoms of poisoning, if large quantities were rapidly formed in the intestine. Derma- tol has no effect on the double sulphates of the urine, so that it apparently does not act as a germicide, but merely as an astringent protective in the intestine. BIBLIOGRAPHY. Meyer u. Stein/eld. Arch. f. exp. Path. u. Pharm., xx., p. 40. Dalcheand Villejean. Arch. gen. de Med., 1887, ii., p. 129. Jasenski. Arch, des Sciences biolog., ii., p. 247. Surveyor and Harley. Brit. Med. Jour., 1895, ii., p. 1483. Fleiner. Centralbl. f. klin. Med., 1893, p. 69 (supplement). Malthes. Centralbl. f. inn. Med., 1894, p. 2. Cramer. Munch, med. Woch., 1896, p. 587. Heinz. Berl. klin. Woch., 1892, p. 1190. Kocher. Volkmann's Klinische Vortrage, No. 224. Petersen. Deutsch. med. Woch., 1883, p. 365. Savdieff. Therapeut. Monatsh., 1894, p. 485. Cerium. Cerium is used to a limited extent in therapeutics in the form of the oxalate. Very little is known of its effects, but it is apparently absorbed with difficulty from the stomach and intestine. It is said to depress the heart, and to induce vomiting and purging, with hyperaBmia and ecchymoses in the stomach and bowel, and nephritis and congestion in the kidney, when it is injected into the blood vessels. In therapeutics it is used in vomiting from seasickness, pregnancy and other conditions, in which irritation of the stomach is not the primary cause. It is quite unknown how it acts in these cases, but it is surmised that its ef- fects are local and similar to those of bismuth subnitrate. Cerii Oxalas (U. S. P., B. P.) (Ce 2 (C 2 O 4 ) 3 +9H 2 O), a white granular powder, tasteless, odorless, insoluble in water or alcohol. 0.1-0.6 G. (2-10 grs.). IX. ALUMINIUM AND ALUM. The chief pharmacopoeial preparation of aluminium is the sulphate of aluminium and potassium, or alum, which has been largely used for its astringent properties. Alum solutions precipitate albumin, but the precipitate is soluble in excess of the proteid. It is not known whether an albuminate is formed similar to those of the heavy metals, though it seems probable that this is the case. Dilute solutions of alum 696 THE HEAVY METALS. have an astringent effect from their throwing down a layer of precip- itated proteid on the surface of the mucous membranes or on wounded surfaces, but larger quantities and more concentrated solutions act as irritants. This is more especially the case when dried alum is applied, for, in addition to its coagulating effect on the proteids, this prepara- tion has a great avidity for water. Symptoms. Alum solutions have a sweetish, astringent taste, and in small quantities induce no symptoms except a feeling of dryness and astringency of the mouth and throat, and some constipation. Larger doses act as gastric irritants and cause nausea and vomiting, and, in extreme cases, purging. Even the largest quantities, however, are followed by no symptoms except those of gastro-intestinal irritation and inflammation, and the long-continued use of alum does not elicit any symptoms of chronic poisoning. The aluminium salts are not ab- sorbed in any quantity from the stomach and intestine, so that no symptoms of general poisoning arise from the internal use of the salt. Aluminium vessels may be used for cooking, or even to contain acids, without danger of intoxication, as has been shown by a recent series of investigations. Aluminium salts, especially the acetate, chloride and some more recent preparations, have very considerable antiseptic power, much more than some of the more generally used antiseptics, such as boric acid. Action. Aluminium has a very remarkable general action when it obtains access to the blood. In Siem's experiments on animals, the sodium- aluminium lactate or tartrate induced a very slow intoxication, mammals never dying from the effects sooner than one or two weeks after the in- travenous injection of the salts. In frogs the symptoms were those of a de- scending paralysis of the central nervous system, the heart and the peripheral nerves and muscles being little affected. In mammals the first symptoms appeared only after three to five days, and consisted in constipation, rapid loss of weight, weakness, torpor and vomiting ; marked abnormalities in movement and sensation were observed later, such as tremor, jerking movements, clonic convulsions, paresis of the hind legs, anaesthesia of the mouth and throat, and lessened sensation all over the body. Before death, diarrhoea often set in, and albuminuria was generally present. The mucous membrane of the stomach and bowel was found swollen and congested, the kidney and liver had often undergone fatty degeneration, and haemorrhages were found in the renal cortex. Aluminium was found in the urine. Like the other members of the heavy metal series, aluminium therefore acts on the bowel and kidney in general poisoning, while many of the symp- toms point to a direct action on the brain. Dollken has recently confirmed Siem's results, and showed that the nerve cells and fibres of the cord and medulla undergo degeneration, particularly those of the lower cranial nerves. It has been stated that the alum salts of the food are absorbed and stored in the bones, but this is incorrect. What little is absorbed is probably rap- idly excreted by the bowel and perhaps by the urine. A metal which is very nearly related to aluminium in its effects in the organism is Beryllium. It differs chiefly in being more poisonous, in being absorbed from the stomach and intestine, and in causing more distinct lesions in these when it is injected into the blood. ALUMINIUM AND ALUM. 697 PREPARATIONS. ALUMEN (U. S. P., B. P.), alum, potassium alum, (A1 2 K 2 (SO 4 ) 4 + 24H 2 O), large, colorless, octahedral crystals, with a sweetish, strongly astringent taste, soluble in water, but not in alcohol. 0.3-1 G. (5-15 grs.). Glycerinum Aluminis (B. P.), 10 per cent. Alumen Exsiccatum (U. S. P.), Alumen Ustum (B. P.), burnt alum, dried alum (A1 2 K 2 (SO 4 ) 4 ), a white, granular powder, attracting moisture on ex- posure to air, soluble in water. Alumini Rydroxidum (U '. S. P.) (A1 2 (OH) 6 ), a white, light, amorphous powder, odorless, tasteless, insoluble in water or alcohol, but soluble in hydrochloric or sulphuric acid and in fixed alkalies. 0.3-1 G. (5-15 grs.). Alumini Sulphas (U. S. P.) (A1 2 (SO 4 ) 3 ), a white, crystalline powder, with a sweetish, astringent taste, soluble in water, not in alcohol. Uses. Alum is used chiefly externally for its astringent properties. It has been employed as an emetic, but is less reliable than the sul- phate of copper or tartar emetic, and very large doses (4-8 G., 1-2 drs.) are required. In diarrhoaa either alum or the hydrate is some- times advised. Alum solution is useful as an astringent gargle (1-5 per cent.), as an injection in gonorrhoea (J-l per cent.), as an astringent lotion in skin diseases (1 per cent.), and for other similar purposes. It is said to tend to cause corneal perforation by dissolving the intercellular sub- stance, but has been used in ophthalmia by many surgeons. Dried alum is more caustic, from its withdrawing fluid from the tissues. It has been used to a limited extent as an emetic ; more frequently as an application to exuberant granulations, haemorrhoids, or condylomata, and as a styptic in bleeding from the nose or teeth. Alum has often been prescribed in chronic lead poisoning with success. A one per cent, solution has been injected into the rectum in chronic dysentery, but is inferior to the nitrate of silver. A large number of aluminium preparations have been introduced recently as antiseptic astringents. Among these may be mentioned alumnol (naph- tol sulphonate of aluminium), salumin (salicylate), tannal (tannate), gallal (gallate), boral (borotartrate), cutol (borotannate), alsol (acetate), alkasal (salicylate of potassium and aluminium). They are used partly in solution, chiefly as dusting powders, but it has yet to be proved that they are supe- rior to the older preparations. As with so many of the products of the new industrial chemistry, they are thrown on the market in such profusion, and are heralded with such exaggerated praise, that it is impossible at present to state which of them are really improvements on the more generally recog- nized preparations, and which are merely adapted to enrich the inventor, without materially advancing therapeutics. BIBLIOGRAPHY. Stem. Inaug. Diss., Dorpat, 1886. DoUIcen. Arch. f. exp. Path. u. Pharm., xl., p. 98. Jalandela Oroix. Ibid., xiii., p. 210. Heinz. Berl. klin. Woch., 1892, p. 1158. (Alumnol.) Plagge u. Lebbin. Ueber Feldflaschen und Kochgeschirre aus Aluminum, Berlin, 1893. 698 THE HEAVY METALS. X. MINOR METALS. Gold. Gold has never been largely used in therapeutics, although repeated at- tempts have been made to introduce it in the treatment of the most diverse conditions ; the salt employed has almost invariably been the double chlor- ide of gold and sodium. It is much less poisonous than many of the other metals and may be taken for many months without entailing any untoward symptoms. The subcutaneous injection in frogs is followed by paralysis of the central nervous system, gold possessing little action on the heart and striated muscles in these animals. Injected intravenously in dogs, it causes vomiting and dyspnoea, which soon pass off, but if sufficient has been in- jected the animal suffers from nausea, vomiting and diarrhoea for several days, eats nothing, loses flesh rapidly, and dies a week or more after the ex- periment. Numerous ulcers are found in the stomach and intestine, and these often betray their presence in life by haemorrhages. Gold lowers the blood pressure somewhat on intravenous injection, probably from the dila- tion of the mesenteric vessels accompanying the intestinal action. It has little effect on the rate of the heart except in large doses, and dilates the vessels when perfused through them. When given by the mouth to dogs and cats, it is at once ejected from the stomach by vomiting. Gold has therefore the ordinary general effects of the heavy metals in causing acute irritation and ulceration of the alimentary canal. The early vomiting may be due to action on the centre, but is more probably caused by its irritating the stomach. The diarrhoea, and the ulceration of the stomach and intestine probably indicate that it is excreted by these organs. Auri et Sodii Chloridum (U. S. P.), a mixture of equal parts by weight of dry gold chloride (AuCl 3 ) and sodium chloride (NaCl), an orange-yellow powder, with a saline, metallic taste, deliquescent in the air and very solu- ble in water. 0.005-0.03 G. (jV- g r -)> i n solution. Gold has been used in various nervous disorders, in particular in those of a hysterical nature, and may conceivably be of value through suggestion, if the patient be informed of the nature of the remedy. It has also been advised in syphilis, rheuma- tism, and other chronic diseases. Of late years it has been widely adver- tised as a specific in chronic alcoholism, but analysis has shown that no gold was contained in the fluid advocated, and there is no reason to suppose that it is of value except by means of suggestion. Kantnack and Calmette have recommended its hypodermic injection in cases of snake bite. BIBLIOGRAPHY. Aronowitsch. Inaug. Dissertation, Wurzburg, 1881. Schultz. Inaug. Dissertation, Dorpat, 1892. Platinum. Platinum resembles gold in its action very closely, but is much more poi- sonous. In the frog it paralyzes the central nervous system, and later the striated muscles. Kebler observed a stage of convulsions precede that of paralysis, the spasms evidently arising from the spinal cord or medulla oblongata. In mammals the symptoms resemble those of gold poisoning in almost every detail. Small quantities of platinum double salts injected in- travenously increase the urine to some extent ; larger injections cause albu- minuria. Platinum was at one time advised in syphilis, but has never been widely used. BIBLIOGRAPHY. Kebler. Arch. f. exp. Path. u. Pharra., ix., p. 137. Cohnstein. Arch. f. exp. Path. u. Pharm., xxx., p. 127. CHROMIUM. 699 Chromium. Chromium is used in medicine in the form of chromic acid and the bichro- mate of potassium, which are both powerful oxidizing bodies in addition to their poisonous action as metallic oxides, fhe former property renders them more irritant and corrosive than most of the salts of the heavy metals. Chromic acid in particular is a powerful caustic, combining the action of a metallic oxide, an acid, and a strongly oxidizing agent. Applied to the skin in substance it corrodes it, but is said to cause less pain than the more pene- trating caustic potash. Even in dilute solution the chromic salts and the acid act as skin irritants, and the caustic effects are shown by skin diseases, and particularly by deep perforating ulcers in persons exposed constantly to the dust of chromic salts in factories. These ulcers arise from any abrasion of the skin, while the acid does not seem to be capable of penetrating the unbroken epidermis. The cartilaginous septum of the nose is also a common seat of ulceration, which eventually leads to perforation. These ulcers arise from the local action of the poison and not from its absorption ; they are said to be almost painless. The inhalation of the dust leads to chronic bronchitis, while that swallowed and absorbed may give rise to nephritis. Symptoms. In acute poisoning, when a large quantity of the acid or of a salt is swallowed, the symptoms are those of gastro-intestinal corrosion, in- tense pain in the throat and stomach, vomiting and purging, with blood in the vomited matter and the stools, collapse and frequently death. The mouth and throat are stained yellow, and the stomach and intestine exhibit the usual appearance of violent corrosive poisoning. The general action of chromic preparations may be elicited in animals by subcutaneous or intravenous injection, or by the administration of smaller quantities by the mouth. The symptoms resemble those caused by the gen- eral action of other metals. In the frog increasing weakness, tremor and eventually paralysis of the central nervous system are induced. In the mammal weakness and slowness in the movements is followed by albumi- nuria, glycosuria, diarrhoea and vomiting. Sometimes twitching of the muscles or even convulsions are seen, and then the weakness passes into general paralysis. The heart seems little affected by chromium, but the blood-pressure falls. After death the stomach and bowel are found con- gested, and the mucous membrane is necrosed and ulcerated in some parts, covered with ecchymoses in others. Hemorrhages are also found in other organs of the body, notably in the heart wall. The kidney is in a state of acute parenchymatous nephritis and often contains deposits of uric acid, and albumin, casts, and often blood cells appear in the urine. In chronic poison- ing interstitial nephritis is said to occur. Chromic acid and its salts are readily absorbed from the stomach and in- testine. They seem to be excreted for the most part through the kidney, to a less extent by the intestinal epithelium probably. In the urine the metal occurs in part in organic combinations. Chromic oxide compounds act in the same way as the chromates, but are much less poisonous. PREPARATIONS. Acidum Chromicum (B. P.), Chromii Trioxidum (U. 8. P.), chromic acid or anhydride (CrO 3 ), forms crystals of dark purplish-red color and metallic lustre, odorless, very soluble in water. When brought in contact with organic sub- stances, such as alcohol, glycerin or sugar, it oxidizes them rapidly and often violently with explosion. Liquor Acidi Chromici (B. P.), 25 per cent. Potassii Bichromas (B. P.), Potassii Dichromas (U. S. P.), bichromate or dichromate of potassium (K 2 Cr 2 O 7 ), forms large, orange-red transparent crystals, with a bitter metallic taste, soluble in ten parts of water. 6-12 mgs. ( T V- gr. ). Chromic acid is used as a caustic application to malignant growths, 700 THE HEAVY METALS. chancres and diphtheritic membranes, to a less extent as an irritant antisep- tic. It has generally been applied by dipping a glass rod into a solution formed by allowing the crystals to deliquesce, or it may be fused on the end of a wire. It has also been advised in 5 per cent, solution as an application to prevent perspiration of the feet and to harden the skin. The bichromate has been recommended recently in certain forms of dys- pepsia in doses of 5 mgs. ( T V gr.) BIBLIOGRAPHY. Priestley. Jour, of Anat. and Phys., xi., p. 285. Gergens. Arch. f. exp. Path. u. Pharm., vi., p. 148. Pander. Robert's Arb. a. d. pharm. Instit. zu Dorpat, ii., p. 1. Hermanni. Munch, med. Wochenschr., 1901, L, p. 536. Kossa. Pfliiger's Arch., Ixxxviii., p. 627. Manganese. Traces of manganese are found in the blood and tissues of man and ani- mals very frequently, but this metal is not an essential constituent of the body, but is apparently absorbed accidentally with the food. The salts of manganese in large quantities cause acute irritation of the stomach and in- testine, like those of the other heavy metals, but no symptoms pointing to effects from the absorption of the metal are observed even when the adminis- tration is continued for a long time. 1 Manganese is absorbed from the ali- mentary tract, however, but only in very small quantity, and it appears to resemble iron closely in its course through the tissues (see page 664). Its general action has been elicited by the hypodermic or intravenous injection of double salts. In frogs manganese injected hypodermically causes a de- scending paralysis of the brain and spinal cord, and later weakens and arrests the heart, while the peripheral muscles and nerves seem unaffected. In mammals large injections induce epileptiform convulsions, particularly in the rabbit and guinea-pig. Smaller quantities, which cause a less acute intoxi- cation, induce in the dog, nausea and vomiting, diarrhoea, weakness, som- nolence, stupor and death from arrest of the respiration. The urine is often increased, and contains bile pigment, and, towards death, albumin and casts. The stomach and bowel present no congestion or ulceration in these cases. Manganese is found in the vomited matter and the stools, in the liver, kidney and intestinal wall, to a less extent in the other organs. In acute poisoning in mammals the blood-pressure falls, from depression and paralysis of the vaso-motor centre, while the heart is affected only much later. In subacute poisoning the darker color of the urine indicates icterus, but this is much more marked when small quantities are repeatedly injected into the subcutaneous tissues, and chronic poisoning induced. In chronic cases the nephritis, which is shown in acute poisoning by albuminuria, is also more developed, the inflammation commencing in the secretory cells of the kidney but later involving the interstitial tissue, if the animal lives long enough. Manganese injected hypodermically or subcutaneously, is excreted chiefly by the intestinal epithelium, to a less extent by the kidney. PREPARATIONS. Mangani Dioxidum Prcecipitatum (U. S. P.). Dose, 0.25 G. (4 grs.). Mangani Sulphas (U. S. P.) (MnSO 4 + 4H 2 O), colorless, or pale rose-colored crystals with a somewhat bitter, astringent taste, soluble in water, not in alcohol. 0.1-0.5G. (2-8 grs.). Mangani Hypophosphis (U. S. P.) (Mn(PH 2 O 2 ) 2 ). 0.2 G. (3 grs.). 1 Symptoms ascribed to chronic poisoning have recently been described by Embden as occurring in workmen in manganese. MANGANESE. 701 Manganese has been advised in chlorosis and especially in amenorrhoea, in which it is believed by many to have a specific action, while others have found it of no value in either of these conditions. In amenorrhcea the per- manganate of potassium is generally prescribed instead of the dioxide or sul- phate, but as it is at once reduced in the stomach, the effect is the same as if pure dioxide was administered. BIBLIOGRAPHY. Harnack. Arch. f. exp. Path. u. Pharm., iii., p. 58 ; xlvi., p. 372. Robert. Ibid., xvi., p. 361. Cahn. Ibid., xviii., p. 129. Stockman. Brit. Med. Jour., 1893, i., p. 942. Embden. Deutsch. med. Woch., 1901, p. 795. Cadmium resembles zinc very closely in its effects. Nickel and Cobalt salts, administered to the frog, cause a curious dark color in the skin, followed by convulsive movements, which at first arise ap- parently from the medulla oblongata and higher centres, and resemble those of picrotoxin, but later are reflex from excessive irritability of the spinal cord. In mammals the usual symptoms arising from the action on the in- testine and kidney are accompanied by tremors and chorea-like movements, later by tetanus, and finally by paralysis. Strongly acid food may form nickel salts when it is cooked in vessels made of this metal, but no poison- ing results, either because the quantity ingested is too small or because it is slowly absorbed from the stomach and intestine. Cobalt nitrate has been recommended as an antidote in prussic acid poisoning, as it forms an insoluble cyanide, but appears to be of little or no value ; the oxide has been applied externally as an astringent, antiseptic powder. Tin salts paralyze the central nervous system in the frog, and later the heart. In mammals, diarrhoea, colic, vomiting and general weakness are observed, along with paralysis of some parts of the central nervous system and stimulation of others, leading to ataxia, stiffness and irregularity of the movements, and occasionally convulsions. The sulphide is said to be de- posited in the lymph spaces of the intestines in the same way as in bismuth poisoning. General poisoning may be induced by the administration of the salts by the mouth, even when there is no corrosion of the mucous mem- brane. Tin is often contained in preserved foods containing acids from being dissolved off the vessels, and is certainly absorbed, for it has been detected in the urine after the use of such articles. Apparently it is not often present in sufficient quantities to induce poisoning, for although some cases of ' ' tin poisoning ' ' are met with in medical literature, in none of them has it been satisfactorily estab- lished that tin was the cause. Chronic poisoning from this cause is unknown, and animals present no symptoms from prolonged treatment with larger quanti- ties of tin than are contained in any preserved foods (Lehmann). Thallium salts seem to resemble those of lead in their effects, but have a powerful depressant action on the heart, and are said to be more poisonous. Richet states that the injection of thallium acetate in animals is followed by a general atrophy of the muscles, especially of those of the jaw and spine, while baldness has followed its continual use in man. Vanadium presents only the ordinary characteristics of metallic poison- ing. The different oxides vary in toxicity, the pyrovanadates being much the most powerful. Molybdenum and Tungsten resemble each other closely, and induce typical metallic poisoning. Uranium, in addition to the ordinary features of metallic intoxication, causes some glycosuria, the sugar often amounting to one per cent, in the urine. This may probably be explained by the recently discovered fact that this metal retards the reduction of the oxyhsemoglobin of the blood, for 702 THE HEAVY METALS. lessened oxidation in the tissues has been shown to cause some glycosuria in a number of instances. Selenium and Tellurium are classed along with sulphur in chemical sys- tems, but the salts of telluric, selenious and selenic acid induce symptoms resembling those of the heavy metals and arsenic in many points, and may be inserted in this series. In the frog the symptoms are those of central nervous paralysis, and later of heart failure. In mammals vomiting, purg- ing, somnolence, dyspnoea, tonic and clonic convulsions have been noted, and the stomach is found somewhat reddened, the mucous membrane of the intestine swollen and dysenteric, while the kidneys seem less affected. The perspiration is prevented by tellurates, apparently from a paralysis of the terminations of the secretory nerves similar to that induced by atropine. An early symptom of poisoning with these bodies is a garlic odor in the breath, and many of the organs are found of a grayish color after death, and possess this odor. Hofmeister has shown that these salts are reduced to metallic selenium and tellurium in the body, and that afterwards methyl compounds (Te(CH 3 ) 2 , Se(CH 3 ) 2 ) are formed. These are volatile, and, ex- creted by the lungs, urine and faeces, give the disagreeable odor. The syn- thesis of methyl -tellurium is one of the few known cases in which a com- pound with methyl is formed in the animal body, and is of great biological importance. All the selenium and tellurium is not excreted in this form, for some of it appears in the urine, and probably in the fasces, in other combina- tions. Tellurates have been advised in therapeutics to prevent excessive sweat- ing, and certainly have tjiis effect, but are not to be recommended, as the strong garlic odor of the breath persists for days or even weeks after one dose. Osmic Acid has been recommended as an injection into the nerves in neuralgia. It is an intensely irritant substance, and seems to induce ne- phritis and diarrhoaa when absorbed. The greater part of the poison is, how- ever, deposited as a black powder at the point of injection, owing to its being reduced by the tissues. BIBLIOGRAPHY. Cadmium. Marme. Ztschr. f. rat. Med., xxix., p. 125. Wheeler. Boston Med. and Surg. Journ., xcv., p. 434. Nickel and Cobalt. Stuart. Journ. of Anat. and Phys., xvii., p. 89. Arch. f. exp. Path. u. Pharm. xviii., p. 151. Rohde. Arch. f. Hygiene, ix., p. 331. Hiibner. Arch, internat. de Pharmacodyn. , ix., p. 339. Tin. White. Arch. f. exp. Path. u. Pharm., xiii., p. 53. Lehmann. Arch. f. Hygiene, xlv., p. 88. Thallium. Luck. Inaug. Diss., Dorpat, 1891. Eichet. Comptes rend, de la Soc. de Biol., 1899, 252. Bullard. Boston Med. and Surg. Journ., 1902 (2), p. 589. Luzzato. Biochem. Centralbl., ii., p. 86. Vanadium. Priestley. Phil. Trans, of Koy. Soc., clxvi., p. 495. Gamgee and Larmuth. Journ. of Anat. and Phys., xi., pp. 235, 251. Dowdeswell. Jour, of Phys., i., p. 257. Tungsten. Bemstein-Kohan. Robert's Arbeit, a. d. pharm. Instit. zu Dorpat, v., p. 42. MINOR METALS. 703 Uranium. Worosckihky. Robert's Arbeit, a. d. pharm. Instit. zu Dorpat, v., p. 1. Chittenden. Studies from the Lab. of Phys. Chem. of Sheffield Scientific School, i., ii., iii. Selenium and Tellurium. Czapek u. Weil. Arch. f. exp. Path. u. Pharm., xxxii., p. 438. Hofvneister. Ibid., xxxiii., p. 198. Gies and Mead. Amer. Journ. of Phys., v., p. 104 ; Philadelphia Med. Journ., 1901, p. 566. PART V. FERMENTS, SECRETIONS AND TOXALBUMINS. I. DIGESTIVE FERMENTS. A NUMBER of digestive ferments have been introduced into thera- peutics for the treatment of gastric and intestinal disorders. The earlier members of the series were proteolytic ferments, intended to reinforce the pepsin of the stomach, but of recent years the amylolytic ferments have also been strongly advocated. Pepsin. The pharmacopeia! preparations of pepsin are generally obtained from the pig's stomach. Their origin is not a matter of indifference, for it has been recently shown that pepsins obtained from different species of animals differ considerably in their behavior towards vari- ous acids. Pepsin digests only in acid solution, the best results being obtained in a solution of 0.2 per cent, of hydrochloric acid. (See Acids, page 561.) In alkaline solution it is inert, and in fact is rapidly de- composed, so that when pepsin and alkaline carbonates or bicarbonates are prescribed together, the effects are due to the alkalies only. Pepsin is used in therapeutics on the theory that the stomach does not secrete enough of the ferment in certain conditions. But it may be questioned whether this is true in even a small proportion of the cases treated with pepsin, for the gastric juice is almost always capable of digesting proteids if it is acid in reaction. In a number of forms of dyspepsia the acid secretion is insufficient, but the ferment is almost always present in quantity, for it digests proteids outside the body as soon as it is acidulated. Pepsin is indicated then only in the rare cases in which the contents of the stomach acidulated with hydro- chloric acid fail to digest proteids. It is very often administered in other forms of dyspepsia, and certainly does no harm, but there is no question that it is entirely unnecessary in the great majority of the cases in which it is prescribed. PREPARATIONS. Pepsinum (U. S. P., B. P.), a proteolytic ferment obtained from the glan- dular layer of fresh stomachs from healthy pigs, and capable of digesting not less than 3,000 times its own weight of freshly coagulated egg albu- min. 1 It is a fine, white, amorphous powder or thin scales, free from 1 The B. P. preparation may be obtained from the pig, sheep or calf and is required to digest 2,500 times its weight of hard-boiled white of egg. 45 705 706 FERMENTS, SECRETIONS AND TOXALBUM1NS. offensive odor and having a mildly acid or saline taste, usually followed by a suggestion of bitterness. It is soluble in about 100 parts of water, but is more soluble if the water is acidulated. 0.3-0.6 G. (5-10 grs.), in powder, or in solution in 0.2 per cent, hydrochloric acid. Pepsin is generally given during or after meals. As has been stated, it is very rarely indicated, as the gastric juice almost always contains sufficient ferment. Ghjcerinwn Pepsini (B. P.) contains hydrochloric acid. A fluid drachm represents 5 grs. of pepsin. 12 fl. drs. Many other preparations of pepsin are used in popular medicine, to a less extent by the profession. Pepsin wines, for example, are often taken as tonics and digestives, but the wine is probably of greater efficacy than the ferment. In these pepsin wines the ferment is not destroyed, however, as is sometimes stated, for pepsin is able to digest proteids in much stronger alco- holic solutions than they represent. Pancreatic Ferments. The pancreatic ferments have also been introduced into therapeutics, generally in the form of an extract of the gland, pancreatin. These ferments differ from pepsin in acting only in alkaline or neutral solu- tion, and besides digesting proteids, form sugar from starch and sa- ponify and emulsify fats. The pancreatic ferments are rendered inert by a comparatively short exposure to the acid gastric juice. The value of pancreatin is even more problematical than that of pepsin, for though it would no doubt be valuable where the digestive ferments, particularly those of the pancreas, were deficient, this has not been shown to occur. On the other hand, the pancreatic ferments are certainly destroyed in passing through the stomach. It has been suggested, however, that they may act in the stomach, if they are given before or with the food, as the acid gastric juice is only secreted slowly, and some time must elapse before the pancreatin is rendered inert. In cases in which there is a deficiency in the acid of the gas- tric juice, the pancreatin might conceivably act throughout the stay of the food in the stomach. Attempts have been made to preserve the pancreatin from the deleterious effects of the gastric juice by adminis- tering it in capsules which are dissolved only in the intestine. It is certainly possible that the pancreatin may be useful in certain cases,' where the ferments of the pancreas are absent and the acid of the stomach so deficient as not to be destructive, but there is no reason to suppose that this series of accidents occurs at all frequently, and it is impossible to diagnose inefficiency of the pancreatic secretion. PREPARATIONS. Pancreatinum (U. S. P.), a mixture of the enzymes naturally existing in the pancreas of warm-blooded animals, usually obtained from the fresh pan- creas of the pig. It forms a yellowish, yellowish-white, or grayish, amor- phous powder, having a faint, not disagreeable odor and a meat-like taste, and is slowly soluble in water. 0.1-0.3 G. (2-5 grs.), in powder or in cap- gules. Keratin capsules have been proposed in order to protect the pancre- atin from the gastric juice. Liquor Pancreatis (B. P.), a liquid preparation containing the digestive DIASTASE. 707 principles of the fresh pancreas of the pig. The preparation is most active when the animal from which it has been obtained has been fed shortly be- fore being killed. Two cubic centimetres of the solution ought to digest 80 c.c. of milk. Benger's Liquor Pancreaticus is a solution of the pancreatic ferments made up with some alcohol. In connection with the digestive ferments may be mentioned ingluvin, an extract of the fowl's gizzard, which was a few years ago highly recom- mended as a remedy in the sickness of pregnancy, but has proved entirely valueless. Vegetable Ferments. Besides these animal digestive ferments, a number of vegetable proteolytic enzymes are known, and have enjoyed a more or less shortlived popularity. Probably many more plant juices are able to digest proteids than are at present generally recognized ; thus many of the bacteria liquefy gelatin and albumin, and the insectivorous plants such as Drosera (sundew) and Dionea secrete a digestive fluid. Figs, pine-apples (bromeliri), the scarlet pimpernal (Anagallis arvensis), and many others of the higher plants have been shown to possess these ferments, but the best known of these is the Carica papaya, or pawpaw, which contains a digestive ferment known as papain, papayotin or papoid. This ferment acts in neutral, moderately acid, or alkaline solu- tion at the temperature of the body and in the cold. When swallowed it has no effect except its digestive action, but injected into the blood, it is said to paralyze the heart and central nervous system, and to cause haemor- rhages into the intestine ; it is very irritant in the subcutaneous tissues, causing pain and high fever. It has been used instead of pancreatin and pepsin in disorders of the digestion, and also as an anthelmintic. Diphthe- ritic membranes have been treated by the frequent application of papain solution (once an hour by some of its advocates, more frequently by others), and apparently with success as far as the removal of the membrane was concerned ; the underlying disease was not favorably influenced, however, and the treatment has been abandoned. Papain solution has also been in- jected by the hypodermic needle into tumors and abscesses, with the intention of digesting the new growth, or accelerating the progress of the abscess towards the surface, but the results obtained do not encourage the further use of the remedy in this way. Peptones are unquestionably formed in the tumors when papain is injected. Several milk-curdling ferments have been found in plants, but none of them have been used in therapeutics. Diastase. Several amylolytic or sugar- forming ferments have been used more or less in therapeutics, the first of these being the diastase or enzyme of malty which is known under the names of malt extract, maltzyme, maltine, etc. When grain is allowed to germinate, its starch is formed into a soluble form (sugar) by means of a ferment known as diastase, and it was supposed that this diastase might aid the digestion of starchy foods in the body. When malt extract is formed at a low temperature, it unquestionably contains diastase and is capable of digesting starch, but many of the extracts on the market are quite inert, the ferment having been destroyed by heat. Those extracts are therefore devoid of digestive power, but form a pleasant, easily digested food. They often contain alcohol, and are then indistinguishable from beer or stout. 708 FERMENTS, SECRETIONS AND TOXALBUMINS. More recently, some other sugar-forming ferments have been brought forward, notably that obtained from Eurotium oryzse, a mould of the aspergillus family. This enzyme is known as taka-diastase from the name of its discoverer, Takamine, and is very much more powerful than any of the malt extracts, as it digests over one hundred times its weight of starch. Taka-diastase has been recommended in cases in which there is supposed to be a deficient digestion of starch. It ceases to act in the gastric juice as soon as the acidity exceeds 0.1 per cent., but may be able to digest a certain amount of starch in the mouth and stomach before it is destroyed. The question at once arises, however, whether the ordinary digestive juices are ever unable to digest the starch of the food. And although a new term, " amylaceous dyspep- sia," has been introduced to indicate this class of cases, if they should be found to exist, it must be admitted that no satisfactory evidence of their existence has been brought forward as yet. It is stated that more starch is found to be digested in the stomach after the administra- tion of diastase, but this seems to be beside the point, for it merely indicates that less starch reaches the intestine for the pancreatic juice to act upon. Until it is shown that in some cases the digestion of starch by the intestinal ferments is insufficiently performed, the diastase preparations would seem to be superfluous. According to Friedenwald, diastase increases the digestion of starch in the stomach chiefly in cases of hyperacidity, but doubt is thrown on this statement by other in- vestigators. BIBLIOGRAPHY. Papain. Hirsch. Therap. Mon., 1894, p. 609. Oswald. Munch, med. Woch., 1894, p. 665. Rossbach. Ztschr. f. klin. Med., vi., p. 527. Martin. Jour, of Phys., y., p. 213 ; vi., p. 336. Younger. Lancet, 1895, i., p. 1050. Chittenden, Mendel and McDermott. Amer. Journ. of Phys., i., p. 255. Pineapple. Chittenden. Jour, of Phys., xv., p. 249. Taka-Diastase. Friedenwald. New York Med. Journ., 1897, May 29. Leo. Therapeut. Monatsh., 1896, p. 635. Strauss u. Stargardt. Ibid., 1898, p. 65. II. BILE. The bile is very seldom used in therapeutics at the present day, al- though it was formerly credited with great healing virtues. It has a bitter taste, and may have some effect like the vegetable bitters, but has no advantage over these, and is not likely to be used to promote the appetite now, although it was formerly used as a stomachic. The bile is found to precipitate the peptones in test-tube experiments, but does not appear to retard digestion in the stomach materially, judging from experiments carried out in a case of gastric figtula. In the intes- tine it is generally believed to act as an antiseptic, chiefly because the BILE. 709 stools have a strong putrefactive odor in cases of retention of bile. Limbourg has also shown that the addition of bile to proteid solutions delays their decomposition, while there is some evidence that it promotes pancreatic digestion. It has some purgative action, as is shown by the obstinate constipation which often occurs when it is prevented from reaching the intestine ; according to Stadelmann, the bile acids irritate the mucous membrane of the large bowel and thus induce purgation. An obscure relation exists between the drastic purgatives and the bile in the intestine, several of them failing to act in its absence. (See page 96.) Bile increases the activity of the fat-splitting ferment of the pancreas and thus augments the absorption of fats. Most of the bile given by the mouth is absorbed in the stomach and small intestine and carried to the liver, which excretes it again, while a small quantity of the bile acids escapes in the urine. In the liver it increases the secretion of both the fluid and the solids of the bile ; in fact, the bile is the only reliable cholagogue known. The constituent which acts on the secre- tory liver cells seems to be the bile acids, and their increase is greater than can be accounted for merely by the excretion of that administered, so that it would seem that they exercise some specific stimulant action on the secretory cells. The bile pigment is also augmented when bile acids are absorbed, owing to the destruction of the red cells of the blood, as the liberated haemoglobin is carried to the liver and there formed into bile pigment. Bile given by the mouth does not cause any symptoms except those from the intestine and liver. When it is injected into the blood, how- ever, it depresses the central nervous system and the heart muscle from its direct action on these organs, and decomposes the red cells of the blood. Muscles and nerves suspended in a solution of bile salts rapidly lose their irritability, and some unicellular organisms are killed and dissolved by them. The poisonous constituent of the bile seems to be the salts of the bile acids, but several authors have stated that the pigment is also active. Fraser has recently discovered that the bile has considerable virtue as an antitoxin. Thus the bile of the venomous snake acts as an antidote to their poison, and the bile of other animals has also some effect in this direction. This antitoxic action is apparently due to the presence in the bile of cholesterin, which forms a loose combination or solution with the toxins and retards their absorption into the cells. It is much more efficient when it is mixed with the poison before its application, than when it is injected after the bite. Frazer adds that the bile is also an antitoxin to other poisons, including those produced by the pathogenic microbes. Others have found that the bile of ani- mals dying of an infectious disease (rinderpest) possesses some curative properties in other animals suffering from the same malady, this being explained by the excretion of the antitoxin in the bile. Bile has been used as a purgative, and it has been particularly recommended in the form of an enema. It does not seem to be reli- able, however, and presents no advantages over soaps and similar sub- stances. 710 FERMENTS, SECRETIONS AND TOXALBUMINS. As a cholagogue it is without rival, but no condition is known in which an increase of the bile secretion is indicated, for though it has been proposed to expel gall-stones by raising the pressure in the gall-ducts by cholagogues, it is found that when the pressure is only slightly in- creased, the secretion is arrested. It is inconceivable that the small rise in pressure could force out an impacted gall-stone. Bile might be used to aid the absorption of fats, particularly when it is deficient in the bowel ; in a case of biliary fistula Joslin found that much less fat and nitrogenous food escaped in the stools when the patient was treated with bile pills, than when no treatment was adopted. PREPARATIONS. Pel Sovis (U. S. P.), ox gall, the fresh bile of the ox. Fel Sovis Purificatum (U. S. P.), Fel Bovinum Purificatum (B. P.), is formed from the fresh bile by the addition of alcohol, filtration and evaporation to pillular consistency. The alcohol is added to remove the mucus of the bile. The pigments may be removed by filtering the watery solution through ani- mal charcoal. Bile is always prescribed in the form of pills made from the purified prep- aration. 0.3-1 G. (5-15 grs.). BIBLIOGRAPHY. Stadelmann. Arch. f. exp. Path. u. Pharm., xxxvii., p. 352. Ztschr. f. Biolog., xxxiv., p. 1. Rywosch. Arb. a. d. pharm. Instit. zu Dorpat, ii., p. 102 ; vii., p. 157. Limbourg. Ztschr. f. phys. Chem., xiii., p. 196. Pfaffand Balch. Journ. of Exp. Med., ii., p. 49. Fraser. Brit. Med. Journ., 1897, ii., pp. 125 and 595 ; 1898, ii., p. 627. Joslin. Journ. of Exp. Med., v., p. 513. Cohnheim. Biochem. Centralbl., i., p. 171. III. INTERNAL SECRETIONS. Until very recently the only animal secretions recognized in thera- peutics were the digestive ferments, the bile, and a few rarely used sub- stances, such as musk. But within the last few years it has been shown that certain glands supply the blood constantly with substances which are necessary to the economy, and a deficiency in which leads to the gravest symptoms. The subject of internal secretion is still in its infancy, but therapeutics has already been enriched with at least two additions of unquestioned value, and may profit still more by the fur- ther exploration of this field. The chief object of " organotherapeu- tics," or the treatment of disease with extracts of the glands of the body (animal extracts), has been to supply a deficiency of the normal secretion. At the same time, it is possible that a wider field of useful- ness may be developed, for there is no reason why these animal extracts should not have a true pharmacological action, as well as the vegetable extracts. Advance in organotherapeutics is not, however, to be ex- pected from the indiscriminate use of the gland extracts in every, sort of disease, such as is too popular at present. Such progress as has been made hitherto in this field has been due to careful observation and experiment, and not to haphazard use of the hypodermic syringe. THYROID EXTRACT. 711 Thyroid Gland. The treatment of certain diseases by the administration of thyroid gland and its extracts is one of the most satisfactory examples of ra- tional therapeutic progress, and the steps which led to its adoption may therefore be briefly mentioned. In 1882-3, Kocher and Reverdin published observations made on patients whose thyroids had been totally extirpated, and who had subsequently presented a series of symptoms to which these observers gave the name of cachexia thyreopriva. They pointed out that this condition resembled in many of its features myxoedema, a disease discovered by Gull some years before and asso- ciated with atrophy of the thyroid gland. These observations were confirmed by a number of authors, who removed the thyroids from animals, and found a cachexia appear in them. The next advance was the discovery that these symptoms in animals could be removed, or at any rate ameliorated, by grafting pieces of thyroid in the peritoneal cavity or subcutaneous tissue. Horsley suggested that myxoedema should be treated in the same way, and Murray soon afterwards intro- duced the treatment of this disease by the subcutaneous injection of thyroid juice. Even in his first case, the results were eminently satis- factory, but it was soon found that the same results could be obtained by administration by the stomach, and a large number of cases have now been recorded in which very favorable results, or even the complete disappearance of the symptoms has followed this medication. These include not only myxoedematous patients, but also cases in which the thyroid was removed by surgical operation, or where its disease gave rise to symptoms. That the favorable results are due to the treat- ment is proved conclusively by the return of the symptoms when it is abandoned. The effect of the thyroid extract could be explained only by the presence of some unknown principle, for the preparation of course con- tained no living cells. In the last few years, numerous researches have been carried out with the object of isolating this principle. 1 It is found in the colloid contents of the gland follicles in the form of a globulin, thyreoglobulin, which may be extracted from the colloid and gives the ordinary proteid reactions, but is characterized by con- taining a small percentage of iodine ; 2 Baumann's detection of this ele- ment in the thyroid gland was the first intimation that it existed in the tissues of the higher animals and man. Thyreoglobulin is not com- pletely saturated with iodine, for it forms a higher combination with it in the test-tube, but then loses its specific action on the animal organ- ism. When it is subjected to artificial digestion it forms albumoscs and an insoluble non-proteid substance known as lodothyrinf which *No attempt is made to follow the chronological order of these researches. 2 Sometimes a thyreoglobulin is found in the gland, which resembles the normal in its reactions, but contains no iodine (Oswald). 3 lodothyrin was at first named Thyroiodin, but this was liable to be confused with thyreoidin, a term used to indicate the simple extract of the gland. 712 FERMENTS, SECRETIONS AND TOXALBUMINS. contains practically all the iodine of the gland. A similar result is obtained by acting on thyroid gland, colloid, or thyreoglobulin with acids. lodothyrin is readily dissolved in dilute alkaline solutions and may be reprecipitated by acids. It contains more iodine than thyreo- globulin of course, but the exact percentage is still a disputed point, for while Baumann originally stated that it contained about ten per cent., others have found it as low as four per cent., and Oswald's analy- sis gives no less than fourteen per cent, for iodothyrin obtained by the action of acids, and about five per cent, for that formed by digestion. Much remains to be done, therefore, before the composition of iodo- thyrin can be definitely settled, but it is certain that it is not a proteid and that it is rich in iodine and nitrogen, while sulphur is present in smaller amount, and phosphorus is not contained in the molecule. The amount of iodothyrin in the gland varies a good deal in differ- ent animals, and in different individuals of the same species. It was at first supposed that in the goitre districts the percentage of iodothyrin in the gland was lower than in healthy areas, and that in cases of goitre the percentage was smaller than in normal individuals, but this seems to be incorrect, no relation existing apparently between the amount of iodine in the thyroid and the presence of endemic goitre. In children less iodine is found* in the gland than in adults, and after middle age it lessens again. Meat diet diminishes the amount of iodine, either because it makes greater demands on the supply, or because too little iodine is ingested in the food. Vegetable foods, especially those con- taining much iodine, such as beetroot and probably the marine algse, increase the iodine of the thyroid gland. Iodine given medicinally also augments it, and not only iodine itself, but various combinations, such as iodoform and iodides. It is not yet determined whether actually more iodothyrin is formed under these conditions, or whether that already present contains more iodine. A number of other constituents have been isolated from the thyroid gland in a condition of greater or less purity, some of them proteids and others crystalline non-pro teid bodies ; but none of them possess the specific action of the gland extract and in fact none of them have been shown to induce any effect at all except those which it may be supposed contained iodothyrin. On the other hand, thyreoglobulin and iodothyrin induce the same effects as the extract both in myxce- dema and goitre in man and in excision of the thyroid in animals. This has been disputed until recently, owing to the fact that in many cases the parathyroid glands have been removed along with the thyroid in animal experiments. Now the removal of the parathyroids in dogs (on which the experiments have generally been performed) leads to a series of symptoms arising from the central nervous system, and these are not affected by thyroid medication. When the thyroid alone is removed, the symptoms are relieved by iodothyrin, thyreoglobu- lin, or thyroid extract. lodothyrin, therefore, represents the whole therapeutic virtues of thyroid extract, although it is possible that the gland may have other functions than its secretion. lodothyriii and THYROID EXTRACT. 713 thyroid extracts are thus used to replace the secretion of the thyroid gland, when it is deficient from any cause. The function of the thy- roid gland is still very obscure, however, although it is now certain that it is of great importance in the metabolism, as is clearly shown by the disastrous results of its removal or atrophy. The results of the injection of the thyroid extract have also thrown much light on the working of this mysterious organ. Action. The thyroid extracts and iodothyrin seem to be devoid of effect in many normal animals and patients, unless when given in enor- mous quantities. In others they cause some unpleasant symptoms, Vvhich occur more especially in myxoedema and goitre. These symp- toms are partly subjective and indefinite, such as headache, wandering pains, or general weakness, while others are evidently due to circula- tory changes, and consist of a feeling of fullness and congestion of the head, palpitation of the heart, and acceleration, sometimes weakness, of the pulse. Tremors in the arms and legs point to changes in the central nervous system, while loss of appetite and diarrhoea indicate that the alimentary canal is not exempt from its influence. Perspira- tion is often complained of, especially in myxoedema, and a rise of temperature also occurs not infrequently. In normal animals iodothyrin injected intravenously in large quan- tities generally accelerates the heart and lowers the blood-pressure somewhat, and even when given by the mouth repeatedly for several days, it causes some acceleration. This acceleration of the heart has been attributed by some investigators to stimulation of the accelerator centre, by others to direct action on the heart ; it does not seem to be due to any changes in the inhibitory apparatus. Loss of flesh and thirst have been observed, even when the appetite is good and sufficient food and water are supplied. The urine is uni- formly increased in amount. A number of observers have found that the continued administration to animals of thyroid preparations in large amounts leads to diarrhoea, muscular weakness, especially in the hind extremities, emaciation, gastro-enteritis, nephritis, and fatty degen- eration of various organs. In other instances no such symptoms have been elicited, the animals remaining perfectly normal after prolonged treatment. Some of the symptoms induced in man by an overdose of thyroid resemble those seen in exophthalmic goitre or Graves' (Basedow's) disease, and exophthalmos has been observed in monkeys to which large amounts of thyroid were given. As may be gathered from the above, great discrepancies occur in the accounts of the effects of thyroid on normal animals. The accelera- tion of the heart and jthe .fall in weight seem to be the most common results. The effects of thyroid extract on the Metabolism have been repeat- edly examined, with very uniform results. One of the most striking features in many individuals is the rapid loss of weight, which often amounts to several pounds per week. Another is the increase in the 714 FERMENTS, SECRETIONS AND TOX ALBUMINS. amount of nitrogen in the urine, which occurs both in goitre and myxoedema, and very often in apparently normal persons. More ni- trogen is excreted in the urine frequently than is taken in the food, that is to say, the iodothyrin leads to the destruction of the proteids of the tissues. If more nitrogenous food be given, however, this may be arrested, and in fact if large quantities of meat be taken, less nitrogen may be excreted than is taken in the food, so that although the patient is losing in weight, he may be actually increasing in nitrogenous tis- sue. If, on the other hand, a patient has been put in nitrogenous equilibrium, and then under iodothyrin begins to excrete more nitro- gen than he ingests, this excessive tissue waste is not stayed by in- creased carbohydrates and fats ; that is, the carbohydrates and fats cannot replace nitrogenous food to the same extent as in normal individ- uals. Iodothyrin has thus a specific effect in increasing the waste of the proteids of the body. But this increased waste of the proteids only accounts for about one-sixth of the loss of weight, the other five- sixths being evidently due to the more rapid oxidation of fats and the removal of fluid from the body. 1 The more rapid oxidation is further evidenced by the increased amount of oxygen absorbed and of carbonic acid exhaled by the lungs in cases of myxoedema and sometimes in obesity and goitre treated with the extract. The removal of fluid from the body, perhaps the most potent factor in reducing the weight in these cases, is shown by diuresis, which occurs in myxredema especially, but also in obesity. This diuresis has been ascribed to some specific action on the kidney, or to the changes in the circulation, but may per- haps be due to the increased excretion of urea and other urinary sub- stances. That the kidney is acted on in some cases is shown by the occasional appearance of albumin in the urine of patients treated with thyroid preparations. The phosphates excreted are increased in the same ratio as the nitro- gen, and the increase is obviously due to the same cause, augmented proteid waste. In some cases sugar has been found in the urine after thyroid treat- ment, and in a considerable percentage of persons it seems to cause a tendency to glycosuria, as is shown by the appearance of sugar in the urine after the ingestion of large quantities of sugar, which would normally be oxidized in the tissues. The uric acid excretion does not seem to be materially affected by thyroid treatment. After iodothyrin has been administered, iodine is found in the urine in the form of iodides, so that the iodothyrin is evidently decomposed, at any rate in part, in the body. The rest of the iodine is taken up by the thyroid gland, and it would appear probable that it enters into 1 Schondorff states that in nitrogenous equilibrium the oxidation of the fats is in- creased before the proteids of the body are attacked, but when the fat destruction has reached a certain point, the proteid waste is also increased. The early augmentation of the nitrogen of the urine does not indicate an acceleration of the proteid metabolism, but is due to the removal of urea and other products, which have been formed in the tissues before the administration of the remedy, but which are now excreted through the increased activity of the kidneys. THYROID EXTRACT. 715 it in the form of iodothyrin, and that no preliminary decomposition occurs here. In regard to their reaction to thyroid medication, individuals vary consid- erably, for many are scarcely affected by it in any way, and this is particu- larly true of children, while others lose weight rapidly, and under larger doses show symptoms of poisoning (thyroidism). These seem to be more easily elicited in goitre and myxoedema than in ordinary cases. On the other hand, in Grave's disease the symptoms are generally aggravated by thyroid treatment, although a few cases are recorded in which it gave relief. Many authorities therefore believe that Grave's disease is due to the over- production of iodothyrin, but this has not yet been proved, although there is considerable support for the theory. FIG. 51. FIG. 52. A case of sporadic cretinism. Fig. 51, before treatment, age 23 months, height 28 inches, cir- cumference of the abdomen 19 inches. Fig. 52 after treatment with thyroid extract for 5% months, height 30 inches, circumference of abdomen 15 inches. (OSLER. ) The fact that ''thyroidism" occurs more frequently in myxcedematous than in normal persons seems difficult of explanation, but it has been sug- gested that the symptoms are due not to the iodothyrin itself, but to the products of its action. It may be supposed that in myxoedema a large amount of some substance accumulates in the tissues, because the iodothyrin is not present in sufficient quantity to decompose it, and that when the thy- roid treatment is commenced, the body is flooded with the products of de- composition and these give rise to symptoms. In normal persons, on the other hand, there is no such accumulation, and iodothyrin therefore induces no symptoms until it is given in such quantity as to induce intoxication it- 716 FERMENTS, SECRETIONS AND TOXALBUMINS. self. In Grave's disease the iodothyrin would, of course, tend to aggravate the symptoms, if these are due to its excessive production. Until more is learned of the action of iodothyrin and of the cause of Grave's disease, how- ever, these explanations are mere hypotheses, and they need not be entered upon farther here. Iodine, as has been stated, increases the iodothyrin of the gland, and this perhaps explains the beneficial effects formerly seen in goitre from the applica- tion of iodine internally and locally. When iodine was efficient in those cases, and any considerable diminution of the gland occurred, it was often accompanied by symptoms exactly resembling those produced by large doses of iodothyrin. Those symptoms were caused by small quantities in some patients, while much larger doses had no such effects in others a fact which gave rise to some discussion and several erroneous theories. Sometimes the acute symptoms passed into a cachexia of very long standing. The quan- tity of iodine required to act in goitre is much greater than the iodine of the iodothyrin necessary, and this shows that the latter acts not merely as an iodine compound, but as the specific substance of the gland. Various iodine compounds, such as iodalbumin and iodospongin (the iodine compound of the sponge) have been shown to be practically inert in goitre. 1 PREPARATIONS. THYROIDEUM SICCTTM (B. P.), GLANDULE THYROIDE^E Sicc^: (U. S. P.), a powder prepared from the fresh and healthy thyroid gland of the sheep. It forms a light, dull-brown powder with a faint, meat-like odor and taste, free from any odor of putrescence. About 16 grs. represent an entire gland. Dose, 0.2-0.6G. (3-10 grs.). LIQUOR THYROIDEI (B. P.), a liquid prepared from the fresh and healthy thyroid gland of the sheep, and containing some phenol. A pinkish, turbid fluid, entirely free from any odor of putrescence. It ought to be freshly pre- pared. 6 c.c. (100 mins.) represent an entire thyroid gland (5-15 mins.). Thyroid medication may be carried out in a number of different ways. The old method of ordering the raw or toasted gland to be taken daily may now be said to be rendered obsolete by more elegant preparations, such as dried thyroid or thyroid extract in powder form or in pills or tablets, or the liquor. These ought not to be prescribed in large quantities as they are liable to undergo putrefaction unless when carefully kept ; iodothyrin tablets have also been introduced, each containing 0.001 G. (gV gr.) or more of iodine. The dose should be small at first (e. 7 TY1 " 1 A 1 1 " *r.Tk Blum. Pfliiger's Arch., Ixxvii., p. 70. Voit. Ztschr. f. Biol., xxxv., p. 116. Cunningham. Journ. of Exp. Med., iii., p. 147. Magnus-Levy. Ztschr. f. klin. Med., xxxiii., p. 269. Donath. Virchow's Arch., cxliv., Supplem. , p. 253. Notkin. Ibid., p. 224. Hellin. Arch. f. exp. Path. u. Pharm., xl., p. 121. 718 FERMENTS, SECRETIONS AND TOXALBUMINS. Howell, Chiltenden, Adami, Putnam, Kinnicutt and Osier. Transactions of the Con- gress of American Physicians and Surgeons, iv., pp. 70-206. Berkeley. Johns Hopkins Hospital Bulletin, 1897, p. 137. Cyon. Pfluger's Arch., Ixx., pp. 126, 511, 643. VerEecke. Arch, de Pharmacodynam., iv., p. 81. Tambach. Ztschr. f. Biol., xxxvi., p. 549. Anderson u. Bergmann. Skand. Arch. f. Physiol., viii., p. 326; xiv., p. 224. Georgiewski. Ztschr. f. klin. Med., xxxiii., p. 153. Haskovec. Arch, internat. de Pharmacodyn. , viii., p. 167. Edmunds. Proc. Eoy. Soc., Ixv., p. 368. Murray. Practitioner, 1901, April. Other Internal Secretions. Extract of the Suprarenal or Adrenal Glands. See p. 463. The extracts of the Pituitary Body or rather of its posterior lobe or in- fundibular body, cause some changes in the circulation, owing to their con- taining two substances which have been termed the pressor and depressor bodies. The arterial tension is increased by the extract or by the pressor body, but the rise is smaller than that induced by suprarenal extract, although it is maintained longer. The renal vessels are not contracted and some diuresis occurs. The heart is slowed, partly through inhibitory action, partly from direct action on the muscle. The depressor body causes a transient fall in the blood-pressure. The hypodermic injection of large quantities of the extract is followed by paralysis in mammals. Schiff found that extract of the hypophysis caused a marked increase in the excretion of phosphates in a case of acromegaly and in a healthy old man, while it had no effect on a younger individual ; he attributes this to the ex- tract tending to increase the destruction of the bone tissue. Acromegaly is generally regarded as being connected in some way with disease of the hy- pophysis, but the extract does not seem to modify the disorder in most cases, although improvement has been stated to occur sometimes. The Thymus Gland has been found to contain minute quantities of an iodine compound, which may be identical with that of the thyroid. Svehla found that the injection of an extract into the veins caused considerable ac- celeration of the pulse with some depression of the blood-pressure. The acceleration was found to be due to direct action on the heart, the fall of the blood-pressure to paralysis of the vaso-constrictors. Very large quantities caused restlessness, collapse and death. Thymus extract has been advised in exophthalmic goitre, and is said to be of some value in a certain number of cases, but does not benefit most patients. The excision of the Pancreas in animals is followed by the appearance of sugar in large quantity in the urine, and in many cases of diabetes in the human subject the pancreas is found diseased, so that this gland seems to secrete some substance which is required by the tissues to enable them to maintain the normal amount of sugar in the blood. Extract of pancreas has therefore been administered in diabetes, but as yet without satisfactory re- sults in the ordinary form of the disease. Bone Marrow extract and Spleen extract have been given in pernicious anaemia in order to increase the number of the red cells, and many other extracts of organs have been proposed, often on the most extraordinary grounds. It was not to be expected that these extracts of brain, heart, liver, kidney, prostate and lung would prove of benefit in the diseases of these organs, and experience has shown that they may without exception be rele- gated to the realms of quackery. One extract deserves mention on account of the attention it has attracted, and the influence it has had on the theory of organotherapeutics the ex- tract of the Testicles. The use of testicular extract was first recommended by Brown-Sequard in 1889, as having a general tonic effect. He was led to OTHER INTERNAL SECRETIONS. 719 this conclusion by the consideration that the sexual power is diminished in advanced life and made the bold step from this, that one of the causes of the woes of old age is the diminution of the internal secretion of the testes ; this elixir of youth might, however, be obtained by extracting the organs in various ways. It is surprising how widely this theory has been accepted, and with what zeal all sorts of preparations of the testicles and ovaries, in- cluding the unaltered human semen, have been used, in therapeutics, and, it must be added in justice to the observers, in experiments upon themselves. While there is no question that the removal of these organs exercises an im- portant influence on a number of organs and tissues, there are no sufficient grounds for believing that the testicular extract has any effect whatsoever except through hypnotic suggestion. Two investigators have recently at- tempted to demonstrate the increase in the muscular strength by means of the ergograph, but the results obtained by means of this instrument in other investigations have proved so deceptive, that little weight is to be laid on their results. Loewy and Richter state that extract of testicle increases the oxidation in the tissues of male castrated animals, but not in normal male animals or in castrated females ; extract of ovary (oophoriri) has a similar effect on the castrated female. Instead of the extract of testicle, spermine, an alkaloid found in the testicle chiefly, but also in a number of other organs, has been proposed by Poehl. According to this author, it is an important factor in the oxidation of the tissues, and a number of symptoms of disease are due to its being precipi- tated in the form of the phosphate and thus rendered inactive, this being especially liable to occur whenever the alkalinity of the blood is reduced in any way. Poehl 's spermine has therefore been advised in a large number of diseases, and in fact is considered by some almost a panacea. His state- ments are not founded on any satisfactory experimental or clinical observa- tions, and have met with little credence from experienced physicians. Sper- mine was at one time supposed to be identical with piperazine but this has proved to be erroneous. BIBLIOGRAPHY. On Pituitary Gland. Schafer and Oliver. Journ. of Phys., xviii., p. 277. HowelL Journ. of Exp. Med., iii., p. 245. Schy. Wien. klin. Woch., 1897, p. 277. Mairet et Bosc. Arch, de Phys. (5\ viii., p. 600. Cleghorn. Amer. Journ. of Phys., ii., p. 282. Schafer and Vincent. Jour. ofPhysiol., xxv., p. 87. On Thymus Gland. Svehla. Arch. f. Exp. Path. u. Pharm., xliii., p. 321. Kinnicutt. Cong, of Amer. Phys. and Surg., iv., p. 157. On Testicular Extract (experimental). Zoth. Pfl tiger's Arch., Ixii., p. 335 ; Ixix., p. 386. Pregl. Ibid., Ixii., p. 379. Loewy u. Richter. Arch. f. [Anat. u.] Phys., 1899, Suppl., p. 174. Dixon. Journ. of Physiol., xxvi., p. 244. On Spermine. Bubis. Therap. Monatsch., 1896, p. 22. Spitzer. Berl. klin. Woch., 1895, p. 695. Poehl. Ztschr. f. klin. Med., xxvi., p. 135. 720 FERMENTS, SECRETIONS AND TOXALBUMINS. IV. TOXALBUMINS. A series of bodies, whose existence has only been recognized in the last few years, but whose importance in medicine is ever increasing, is that of the poisonous proteids or toxalbumins. The idea that a proteid can pro- duce dangerous or even fatal symptoms, or act in any way except as a food, dates only from 1884, but many of the animal poisons are now believed to be of proteid nature, and the toxins formed by the micro-organisms of disease are almost certainly of the same general class. The description of most of these must be relegated to the text-books on bacteriology and pathology, but some toxalbumins which are associated with drugs in daily use deserve short mention. Ricin is an intensely poisonous globulin found in the seeds of Ricinus communis along with castor oil, which does not itself contain this principle, however. Ricin is poisonous in doses of about ^V milligram ( T ^V(7 g r -) per kilogram body weight when it is injected into the blood, and is somewhat less poisonous when applied subcutaneously, but seldom causes any symp- toms when swallowed, as it is apparently destroyed for the most part by the digestive ferments. It is thus among the most powerful of the vegetable poisons when it is injected directly into the blood. Death often occurs only several days after the injection in animals, and in the interval no symptoms make their appearance except some loss of appetite, and towards the end, diarrhoea and vomiting. Post-mortem, the bowel is found inflamed and congested and contains ecchymoses ; blood is found in the serous cavities, and extravasations may occur in various other organs, although not so uniformly as in the bowel. Among the most obvious lesions are the innumerable ecchymoses in the great omentum and the swelling of the abdominal lymph-glands, which generally contain numerous small haemorrhages. Microscopical examination reveals small foci of necrosed tissue in the liver, spleen, intestine, stomach and other organs. Ricin seems to be ex- creted by the intestinal epithelium, which may explain the violence of its action here, although it acts as a poison in many other tissues. It is a powerful irritant, inducing inflammation and suppuration when it is injected subcutaneously, or is applied to the conjunctiva. On the other hand it has little or no irritant action on the mouth and throat, and is digested and rendered harmless in the stomach. The mucous membrane of the nose is irritated by the inhalation of the powder in many persons. This toxoglobu- lin has a very characteristic action on the blood. When a drop of a dilute solution is added to a test-tube of defibrinated blood, the corpuscles soon fall to the bottom, leaving the clear serum above, and the blood does not filter through paper any longer, the corpuscles all remaining on the filter, the serum passing through colorless. This is due to the agglutination of the red cells, which are formed into masses and thus fail to pass through the pores of the filter. Fibrin does not seem to be formed in the process, as was at one time supposed, but the nature of the cementing substance is unknown. Stillmark supposed that ricin formed these masses of red cells in the blood vessels, and that the symptoms were due to the emboli resulting, but this is certainly in- correct, for the blood of immune animals reacts in the same way, yet these are not poisoned by many times the usual fatal dose of ricin. Ehrlich found that animals rapidly acquired immunity to the action of ricin, if they received for some time small non-toxic doses. From this dis- covery has arisen the whole of serum-therapeutics, which plays such an im- portant role in medicine at the present time. By gradually increasing the daily amount of ricin, rabbits have attained an immunity of 5,000, that is, they are not affected by 5,000 times as much ricin as would have killed them had no preliminary treatment been instituted. This immunity is en- tirely different from the tolerance acquired for morphine and other drugs, TOXALBUMINS. 721 for the latter is due to the cells of the body becoming accustomed to being constantly bathed in a fluid containing the alkaloid. The same tolerance is acquired by various marine animals, which would be killed if suddenly changed to fresh water, but which are gradually acclimatized, if the change is made more gradually by adding increasing proportions of fresh water to the sea water of the aquarium. The immunity acquired for ricin and other toxalbumins is, on the contrary, due to the formation in the body of a sub- stance which antagonizes the original poison, and which is known as an antitoxin, in this case antiricin. This antagonistic substance circulates in the blood, and can be withdrawn from the immune animal and injected into a second, which then acquires a certain degree of immunity, although less than that of the first. In tolerance, then, the tissues become indifferent to the poison; in immunity they form an antitoxin. Antiricin is antagonistic only to ricin ; it does not protect an animal from any other toxalbumin. Ricin and antiricin are not used in therapeutics, but ricin has repeatedly given rise to poisoning, from the beans being taken as a substitute for the oil. Cattle have also been poisoned by being fed on the refuse of castor oil beans after the oil had been expressed. Another vegetable toxalbumin which resembles ricin very closely in its effects is Abrin, which is obtained from the seeds of Abrus precatorius or je- quirity, the familiar scarlet and black beans, which are often formed into necklaces. Abrin contains two poisons, a globulin and an albumose, of which the former is the more powerful. It induces the same symptoms as ricin, but is less poisonous, and immunity can be acquired in the same way. Animals which are immune to ricin are not more resistant to the ac- tion of abrin than others, because the two poisons form different antitoxins. Abrin or jequirity has been used as an irritant to the eye in cases of granu- lar lids and of corneal opacities. It causes an acute inflammation which improves the condition in some cases, but it must be regarded as an exceed- ingly dangerous remedy, as the inflammation is entirely beyond the control of the surgeons. In animals the eye is often completely destroyed by the application of abrin, while in other experiments enough of the drug is ab- sorbed to cause fatal poisoning. Crotin is another toxalbumin, which is found in the Croton Tiglium, but which does not pass into croton oil. It is less poisonous than ricin and ab- rin, but resembles them in most other points, except that it does not cause agglutination of the blood cells of certain animals, while ricin and abrin have this effect in all kinds of blood hitherto examined. Many other plants contain toxalbumins, but none of them have aroused so much interest as those mentioned above. Many animals produce proteid poisons, such as the snakes, the poisonous lizard, Heloderma suspectum (Gila monster), several amphibia and fish, and the scorpions and spiders (tarantula). On the other hand, several insect poisons which resemble these poisons in their irritant action and in some other points, have been shown not to be proteids. An antitoxin for snake poison has been introduced recently under the name of antivenin, and is found in the bile of poisonous snakes and in smaller quantities in that of other animals. These animal poisons and the bacterial poisons, however, can be treated of with advantage only in special text-books. BIBLIOGRAPHY of Kicin, Abrin and Crotin. Stillmark. Arb. a. d. pharm. Instit. zu Dorpat, iii., p. 59. Martin. Proc. Koy. Soc., xlii., p. 331 ; xlvi., p. 94. Hellin. Inaug. Diss., Dorpat, 1891. Ehrlich. Deutsch. med. Woch. , 1891, Nos. 32 and 44. Flexner. Journ. of Exp. Med., ii., p. 197. El/strand. Robert's Gorbersdorfer Veroffentlichungen, i., p. 1. Midler. Arch. f. exp. Path. u. Pharm., xlii., p. 302. Jacoby. Ibid., xlvi., p. 28 ; Beitrage z. Chem. Phys. u. Path., i., p. 51. 46 722 FERMENTS, SECRETIONS AND TOXALBUMINS. V. COD-LIVER OIL. Cod-liver oil has been long used by the fishermen of the North Sea as a remedy in children's diseases, and was introduced into medicine in the beginning of last century, but became generally used only in the last fifty years. It is obtained from the liver of the cod-fish (Gadus morrhua), and probably from other members of the genus. Formerly the livers were left to decompose, and the oil set free by the breaking up of the cells was collected. It had a most disagreeable odor and taste, however, and many patients could not be induced to take it, while those who were courageous enough to swallow it, often suffered from eructation and diarrhoea afterwards. This method was therefore soon replaced by the " steam-process," in which the oil is melted out of the fresh livers, yielding an oil of much lighter color, and with much less dis- agreeable smell and taste. Quite recently a new process has been intro- duced, by which the oil is extracted by steam, without being exposed to the air, and it is stated that oil thus obtained is less disagreeable than any other. The cod-liver oils used in therapeutics differ considerably in appear- ance and in composition, the older preparations being brownish in color, and having a strong fishy odor and a somewhat acrid, disagree- able taste, while the oil prepared by the more recent process is pale yellow in color, and has much less odor and a bland taste. Cod-liver oil probably contains the ordinary constituents of an ani- mal fat, olein, stearin and palmitin, but the relative proportion in which these are present is unknown. Some free fatty acid is gener- ally found in it, the darker preparations containing some 4-7 per cent., the pale yellow oil less than one per cent, as a general rule. Iodine and bromine are present in traces, apparently very much smaller in amount than is generally believed. The usual statement is that 0.03- 0.04 per cent, of iodine and 0.003-0.005 of bromine exists in the oil, but some oils have been found to contain only about one-hundredth of this amount of iodine. Phosphorus is found in traces in some oils, in an organic combination, not in the free state. A small percentage of cholesterin is often, not invari- ably present, and bile acids and pigments have been said to occur, but this seems incorrect. A number of bases have been found in ood-liver oil by Gautier, especially in the darker colored varieties, while the pale yellow oil contains little or none. These bases or alkaloids (leucomaines) are Butylamine (C 4 H U N), Amylamine (C 5 H 13 N), Hexylamine (C 6 H 15 N), Dihy- drolutidine (C 7 H U N) and two new non-volatile ones, Assellne and Morrhuine. They were found combined with morrhuic, formic, butyric and other acids. Trimethylamine has also been said to occur in it. Cod-liver oil has no very distinct action when taken in ordinary doses, while in large quantities it has a tendency to cause eructation, nausea and diarrhrea. Taken repeatedly, it increases the weight and strength, and improves the general condition. The same effects are obtained in healthy persons by the use of good food and fats, but deli- cate patients who are unable to digest ordinary animal fats, are able COD-LIVER OIL. 723 to take cod-liver oil. Its effects are obviously those of an easily as- similable food, and it is not a drug in the ordinary sense of the term, and has therefore no place in pharmacology properly speaking, but should be classed along with other foods. It is always treated of as a drug, however, because it has often been supposed to have some spe- cific effect quite apart from ordinary foods. It is generally believed to differ from ordinary fats in being more readily assimilable, but the explanation of this fact is by no means agreed upon, for though it is often said to be more rapidly absorbed from the intestine, there is lit- tle reliable evidence that such is the case. A few experiments have been carried out, but by no means enough to establish the truth of the statement satisfactorily, and the chief argument brought forward in its support is that cod-liver oil forms an emulsion in the test-tube more rapidly than other oils. It is undoubtedly well borne by the stomach, but it has not been often compared with other oils in regard to this point, and it is still impossible to state that other oils adminis- tered with the same care as cod-liver oil are not equally successful remedies. Buchheim explained that cod-liver oil formed an emulsion rapidly on account of the free acid it contained, and this has generally been put forward as accounting for its effects in therapeutics. As far as regards the old dark-colored oils, this explanation may hold good, but the pale oil now used in therapeutics often contains less free acid than ordinary olive oil. Some enthusiastic supporters of Buchheim's theory have, therefore, asserted that the pale oil does not give the same results as the older, less pure, acid preparations, but this is not the general opinion of the medical profession. The older explanations started from the view that cod-liver oil is a drug, that the oil itself is only a means to administer certain active principles contained in it. Thus iodine and phosphorus were in turn supposed to be the essential constituents, but have both been shown to be present in too small quantities to be of any effect. More recently cholesterin has been suggested as the curative agent, but it is present in smaller quantities in cod-liver oil than in many other foods. Lastly the bases have been credited with lending cod-liver oil all its vir- tues. But the pale oil contains only traces of these, and again the state- ment has been made that the brown oil is superior. An attempt has been made to support this theory by examining the urine of persons under treat- ment with the bases separated from the oil. The urine has been found in- creased in amount, the urea augmented, the less oxidized forms of nitrogen diminished, but these experiments are of no value, because apparently no measures were taken to keep the amount of food ingested constant. Several substitutes for cod-liver oil have been proposed, such as Lipanin (v. Mering), which is formed from olive oil by the addition of 6 per cent, of oleic acid, and which was suggested by the theory that cod-liver oil owes its rapid absorption to the presence of free acid. A mixture of cacao butter and oleic acid has also been introduced, as well as oil of sesame and olive oil. On the theory that the bases were the indispensable part of the oil, Morrhuol, a crude mixture of bases, acids and pigment, has been introduced into therapeutics and used to some extent, but it has not proved a substitute for the oil in practice. Lipanin has been used only to a limited extent, and has not been able to supplant cod-liver oil, although, like oil of sesanus and 724 FERMENTS, SECRETIONS AND TOXALBUMINS. olive oil, it has the advantage of being much less disagreeable in smell and taste. This may perhaps be due to the conservatism of the medical profes- sion, rather than to the special merits of cod-liver oil. On the whole, cod-liver oil has not been shown to have any action apart from that of an easily digested food, and its superiority to some other fats and oils has not been satisfactorily established. PREPARATION. OLEUM MORRHTJ^E (U. S. P., B. P.), cod-liver oil, Oleum Jecoris Aselli, a fixed oil obtained from the fresh livers of Gadus Morrhua and of other species of Gadus, a pale yellow, thin, oily liquid, with a peculiar, slightly fishy, but not rancid odor, and a bland slightly fishy taste. 4-16 c.c. (1-4 fl. drs.). Emulsum Olei Morrhuce (U. S. P.), 50 per cent. 8 c.c. (2 fl. drs.). Emulsum Olei Morrhuce cum Hypophosphitibus (U. S. P.), 50 per cent, cod-liver oil. 8 c.c. (2fl. drs.). Therapeutic Uses. Cod-liver oil is used in chronic wasting diseases, such as tuberculosis, scrofula, rickets and some forms of syphilis. It is especially beneficial in the earlier stages of pulmonary phthisis, but has no specific virtues here or elsewhere apart from those of an easily digested fat. In all forms of malnutrition and delicacy in children, it is largely used, and undoubtedly causes a considerable increase in weight, but care must be taken that it does not disturb the digestion, especially if the darker oils are used. In some persons pure cod-liver oil always induces nausea, but a much larger number refuse to take the brown oil. In most cases the light-colored oil is taken readily, especially if the dose be small at first (a teaspoonful). When there is dyspepsia or a tendency to diarrhoea, cod-liver oil should be given with caution, and it is generally prescribed only in cold weather, as it is found that patients have a distaste for it in summer. When fever or acute disease is present, cod-liver oil is generally found of little value, perhaps on account of the disturbed condition of the digestion. Cod-liver oil should not be forced on patients ; when it continues to induce nausea and eructation after a fair trial, it should be abandoned. Innumerable means have been proposed to conceal the odor and taste, but it is generally conceded that when possible the pure oil is better given alone. When patients cannot be induced to take it in this way, some volatile oil, ether, or brandy may be added to it; saccharine has also been used to sweeten it. Creosote is sometimes mixed with cod-liver oil in cases of phthisis, or an emulsion is formed containing cod-liver oil, some flavoring substance, iron, hypophos- phites or calcium. Extract of malt and cod-liver oil form a common mixture, and are the basis of many patented emulsions. In general, the pale oil is preferred, but it must be added that some physicians persist in the use of the darker forms, which contain more bases and more free acid, but have a much more disagreeable taste and smell, and are more liable to disturb the digestion. Of the substitutes for cod-liver oil, lipanin has little taste and is generally taken readily. PHLOEIDZIN. 725 It may be given shaken up in inilk or formed into an emulsion. Olive oil is equally valuable and is generally considered more palatable. BIBLIOGRAPHY. Naumann. Arch, der Heilkunde, 1865, p. 536. Buchheim. Arch. f. exp. Path. u. Pharm., iii., p. 118. V. Merino. Therap. Monatsh., 1888, pp. 49 and 233. Salk&wsfd. Ibid., 1888, p. 230. Hauser. Ztschr. f. klin. Med., xiv., p. 543 ; xx., p. 239. Lowenthai. Arch. f. Anat. u. Phys., 1897, p. 258. Mersereau. New York Med. Journ., 1899, ii., p. 11. Sternberg. Ztschr. f. klin. Med., xxii., p. 295. Bouillot. Compt. Kend. de 1'Acad. des Scien., cxv., p. 754. Gautier et Mourgues. Les Alcaloides de Huile des Foies de Morue, Paris, 1890. Heyerdahl. F. Pekel Molar's Cod-liver Oil and Chemistry, London, 1895, p. 88. WeUs. Brit. Med. Journ., Oct. 18, 1902. VI. PHLORIDZIN. 1 Phloridzin is not used in therapeutics, but has attracted some attention from its effects in animals, and may therefore be mentioned shortly. It is a glucoside (C 21 H 24 O 10 + 2H 2 O) found in the rootbark of the apple, pear, cherry and plum tree. When given in large quantities by the mouth it sometimes causes some diarrhoea in animals, but apart from this its only effect is glycosuria, which also follows its injection subcutaneously or intra- venously. The urine is found to contain 5-15 per cent, or even more of sugar, sometimes along with acetone and oxybutyric acid, so that the intox- ication seems at first sight to resemble diabetes mellitus in man very closely. Phloridzin induces the same results in man, and the glycosuria is not accom- panied by any other symptoms generally. It differs from true diabetes, however, in the fact that the sugar of the blood is not increased in amount. The glycosuria is not due to any change in the general metabolism of the body, therefore, but to some alteration of the renal epithelium, by which the blood sugar escapes into the urine instead of being retained in the body and used as a source of energy. This has been definitely proven by Zuntz, who showed that when phloridzin was injected into one renal artery, the urine secreted by the corresponding kidney contained sugar, while that from the other remained normal for some time. As the available sugar is drained off* in the urine, the tissues rapidly manufacture more and pour it into the blood. As long as sufficient food is given, the loss of sugar does not seem to entail any increase in the destruction of the proteid tissues, but when phlo- ridzin is given to starving dogs, the waste of sugar has to be made up from the tissues, and the nitrogen of the urine accordingly rises in amount, while at the same time the liver cells become infiltrated with fat globules. The statement that the sugar of the milk is increased by phloridzin has proved to be incorrect. Glycosuria may be maintained for an indefinite time if the administration of phloridzin be continued, and animals recover rapidly when the treatment is stopped. The glucoside is probably excreted in the urine unchanged, although this has not been quite satisfactorily demonstrated as yet. Phlo- ridzin may be decomposed into a sugar, phlorose, and phloretin, which also induces glycosuria. Syzygium Jambolanum, or Jambul, a tree growing in South America and in the East Indies, is said to contain some unknown substance which has a spe- cific action in diabetes. Several clinical observers have noted improvement in some cases, but others have seen no result whatever follow, and as a general 1 Phloridzin is not in any way related to the other drugs of this part, and has only been inserted here because no suitable position could be found elsewhere. 726 FERMENTS, SECRETIONS AND TOXALBUM1NS. rule no sufficient estimation of the sugar of the urine was made in the cases in which the treatment was believed to be successful. Some experiments on animals seem to indicate that it modifies the sugar formation in the tissues, but cannot be accepted until they are confirmed by further research. BIBLIOGRAPHY of Phloridzin. V. Mering. Zts. f. klin. Med., xiv., p. 405 ; xvi., p. 431. Rosenfeld. Ibid., xxviii., p. 256. Zuntz. Arch. f. Anat. u. Phys. (Phys. Abth.), 1895, p. 570. Coolen. Arch, de Pharmacodynam., i., p. 267 ; ii., p. 255. Kulz, Wright, Moritz, Prausnitz, Cremer, Hitter, Lusk. Zts. f. Biol., xxvii., xxviii., xxix., xxxvi. Reilly, Nolan and Lusk. Am. Jour, of Phys., i., p. 395. Levene. Jour, of Exp. Med. , ii. , p. 107. Pappenheim. Arch. f. Verdauungskrank., iii., p. 421. Imdebrandt. Virchow's Arch., cxxxi., p. 26. Pavy, Brodie and Siau. Journ. of Phys., xxix., p. 467. LoewL Arch. f. exp. Path. u. Pharra., 1., p. 326. PART VI. MENSTRUA AND MECHANICAL REMEDIES. Oleum Theobromatis (U. S. P., B. P.), cacao-butter, a fixed oil expressed from the seeds of Theobroma cacao, forms a yellowish-white solid having a faint, agreeable odor and a bland, chocolate taste. It melts a little below the temperature of the body. Cacao-butter is used almost exclusively to form suppositories, in which astringents and other remedies are incorporated. When these are introduced into the rectum, they melt and the active prin- ciple is liberated. Keratin (not official) is a substance obtained from horns, hoofs, nails, etc., which is insoluble in the gastric juices, but is dissolved by the alkaline pan- creatic secretion. It is used to coat pills which it is desired to protect from disintegration in the stomach. Kaolinum (B. P., U. S. P.), or porcelain clay, is used in the formation of pills containing easily reduced bodies, such as silver nitrate or potassium per- manganate. Mixed with the ordinary vegetable excipients, such as confection of roses, or extract of liquorice or gentian, these salts would be reduced at once. Kaolin is an aluminium silicate and forms a soft whitish powder insoluble in water or dilute acids. Gataplasma Kaolin! (U. S. P.), kaolin moistened with glycerin and applied as a poultice. Sapo (U. S. P.), Sapo Duras (B. P.), hard soap, white Castile soap, is pre- pared from soda and olive oil. Sapo Mollis (U. S. P., B. P.), soft soap, sapo viridis, a soap made from potash and olive oil. Sapo Animalis (B. P.), curd soap, soap made with sodium hydroxide and a purified animal fat consisting chiefly of stearin ; it contains about 30 per cent, of water. These soaps are used in therapeutics as ingredients of liniments and plas- ters. Water containing soap is often thrown into the rectum as an enema, and in infants a soapstick inserted into the anus generally provokes evacua- tion of the bowels in a few minutes. Soaps impregnated with antiseptics, such as perchloride of mercury, car- bolic acid, tar, or iodine, are often used to disinfect the hands. The chief preparations in which soap is used in the pharmacopoeias are : Emplastrum Saponis (U. S. P., B. P.), soap plaster. Linimentum Saponis (U. S. P., B. P.), soap liniment. Linimentum Saponis Mollis (U. S. P., B. P.). The liniments consist of alcohol with soap in suspension, perfumed with volatile oils, and are mildly irritant to the skin. They are used largely as bases for other liniments. The use of the oils, fats and glycerin as vehicles for the application of remedies to the skin has been mentioned already (page 49). They may also be used to dissolve remedies which are insoluble in water, but which are to be given by the mouth, such as phosphorus (in oil). Wax (cera alba, cera flava) is used chiefly to increase the consistency of ointments. A special series of preparations somewhat stifFer than the oint- ments are the cerates of the U. S. P. Plasters are sticky adhesive substances which are chiefly used to give me- chanical support, but which are often impregnated with active remedies in order to elicit their local action on the skin. The basis of many of the plas- 727 728 MENSTRUA AND MECHANICAL REMEDIES. ters is lead plaster, which is obtained by the action of lead oxide on olive oil and consists for the most part of lead oleate. Emplastrum Plumbi (U. S. P., B. P.), lead or diachylon plaster. Emplastrum Adhcesivum (U. S. P.), Resince (B. P.), adhesive plaster. Emplastrum Saponis (U. S. P., B. P.), soap plaster. Emplastrum Opii (U. S. P., B. P.), opium plaster. Emplastrum Belladonna (U. S. P., B. P.), belladonna plaster. Emplastrum Picis (B. P.), Burgundy pitch plaster. Emplastrum Capsici (U. S. P.). Emplastrum Calefaciens (B. P.), warming plaster. Emplastrum Cantharidis (B. P.). Emplastrum Hydrargyri (IT. S. P., B. P.), mercury plaster. Emplastrum Ammoniaci cum Hydrargyro (B. P.). Emplastrum Plumbi lodidi (B. P.). Emplastrum Menthol (B. P.). Court plaster is formed from isinglass, the dried swimming bladder of sev- eral species of sturgeon, which is dissolved in water, alcohol and glyeerin and painted on taffeta. Isinglass differs from lead plaster and its deriva- tives in being transparent, so that if it be spread on a flesh-colored cloth, it disfigures the hands and face less than the others. Lead plaster, resin plaster and isinglass plaster are used only to cover and protect cuts and abrasions, and to keep the edges of wounds in apposition. The adhesive plaster and isinglass plaster are superior to lead plaster, as they stick more firmly. It is perhaps unnecessary to add that plasters are alw r ays applied spread on cloth. Opium and belladonna plasters are believed to lessen pain locally as well as to give support, but this is perhaps imaginary. Belladonna plaster is said to lessen the secretion of perspiration and of milk. The pitch, arnica, menthol and capsicum plasters have some irritant action and this is of course more marked in the case of the warming plaster and cantharides plaster. Some mercury is absorbed when the mercury plasters are applied to the skin, but this method of administration allows of even less accurate dosage than inunction, and is seldom used. Iron plaster is devoid of any properties apart from those shared with the others. Another series resembling the plasters in their sphere of usefulness is formed by the Collodia. Their basis is pyroxylin, or soluble gun-cotton, which is formed from cotton by the action of sulphuric and nitric acids, and which consists of a mixture of nitrates of cellulose. Collodion is formed by dissolving pyroxylin in a mixture of alcohol and ether. When these evapo- rate, there remains a fine layer of pyroxylin, which protects the surface to which it is applied and gums the edges of slight cuts together. This collodion is rendered less brittle by the addition of Canada turpentine and castor oil in small proportions, and is then known as flexible collodion. A blistering collodion is formed by the addition of powdered cantharides to the flexible preparation. Another preparation contains tannic acid. Pyroxylinum (U. S. P., B. P.), soluble gun cotton, colloxylin. Collodium (U. S. P., B. P.), collodion. Collodium Flexile (U. S. P., B. P.), flexible collodion. Collodium Cantharidatum (U. S. P.), Collodium Vesicans (B. P.), blistering collodion. Collodium Stypticum contains 20 per cent, of tannic acid. Instead of collodion, india-rubber, Caoutchouc (B. P.), Elastica (U. S. P.), may be dissolved in chloroform and applied in the same way. Calcii /Sulphas Exsiccatus (U. S. P.), Dried Gypsum, used to impregnate bandages, which then become hard and immovable. CLASSIFICATION OF DRUGS ACCORDING TO THEIR THERAPEUTIC USE. I. Drugs applied for their local action to the skin, wounds, or visible mucous membranes. Corrosives or caustics. Potash, 540 Mercury nitrate, 650 Potassium and sodium carbonate, 540 Silver nitrate, 686 Zinc chloride, 684 Nitric acid and other acids, 555 Chromic acid, 699 Burnt alum, 695 Bromine, 582 Arsenic, 603 Lead nitrate, 670 Trichloracetic acid, 563 Ammoniated mercury and other mercury preparations, 650 (Soda, 540) (Sodium ethylate, 545) (Lime, 564) (Carbolic acid, 393) Disinfectants and antiseptics. Hydrogen peroxide, 587 Permanganate of potassium, 589 Chlorine, 582 Sulphurous anhy- dride, 562 Formaldehyde, 423 Carbolic acid, 393 Corrosive sublimate and other mercury salts, 650 Silver nitrate, 686 Zinc chloride, 684 Boracic acid, 578 lodoform, lodol, 517 Cresol, 399 Tar, 405 Salicylic acid, 408 (Benzoic acid, 419) (Camphor, 426) (Sulphites, 529) (Sulphocarbolates, 417) (Volatile oils (thymol, eucalyptol, etc.)) Astringents. Tannic acid series, 109 Iron preparations, e. g., sulphate, 655 not applied to living objects. II. Bismuth preparations, 692 Lead acetate, 670 Zinc sulphate and oxide, 683 Copper sulphate, 680 Alum, 695 Styptics. Soluble astringents (see above). Iron perchloride, 655 Silver nitrate, 686 Burnt alum, 695 To contract vessels and reduce hemorrhage and swelling. Cocaine, 298 Suprarenal extract (adrenalin), 458 Emollients or protectives. Emollients, 49 Plasters and Collodia, 728 Dusting-powdersstarch, talcum, chalk, and many insoluble me- tallic powders, which may also be slightly astringent, 53. Local anodynes and analgesics for pain and itching. Bicarbonate of potassium, 541 Cocaine, Eucaine, Orthoform, etc., 298 Carbolic acid, 393 Chloretone, 186 Prussic acid, 238) Atropine, 276) Aconite, 328) Veratrine, 388) Local anaesthetics. Cold by evaporation of ether, etc., 181 Cocaine and Eucaine, 298 Drugs used for affections of the alimentary tract. MOUTH AND THROAT (see Section I.). Demulcents, 45 Chlorates, 522 Ammonium chloride, 496 Cubebs, 75 To lessen salivation. Atropine, 276 729 730 THERAPEUTIC CLASSIFICATION. Flavoring substances. Sugars, 54 66 eugars, 01 Volatile oil series, Acids (citric), 554 Syrup of Tolu, Ginger, etc. STOMACH. Pepsin, Papain, etc., 705 Hydrochloric acid, 561 Emetics. Common salt, 486 Mustard, 88 Warm water. Apomorphine, 234 Ipecacuanha, 339 Tartar emetic, 629 Copper sulphate, 682 Zinc sulphate, 686 (Alum, 696) (Ammonium carbonate, 551) To lessen irritation and vomiting. Opium, 206 Chloral, 186 Lime-water, 565 Bismuth, 692 Cerium oxalate, 695 Cold (ice). Cocaine, 298 Carbonic-acid water, 580 Demulcents, 45 (Prussic acid, 238) To lessen acidity, antacid's. Potassium and Sodium car- bonate and Bicarbonates, 540 Magnesia and Magnesium car- bonate, 540 Lime-water and chalk, 565 Lithium carbonate, 540 To increase secretion, bitters. Simple bitters, 56 Nux vomica, Strychnine, 195 Cinchona and Quinine, 353 (Hydrastis, 229) (Salicin, 413) Carminatives. Volatile oil carminatives, 61 Alcoholic preparations. Carbonic acid waters, 580 Carbonates and Bicarbonates, 540 Bitters (see above). Camphor, 426 Charcoal, 577 Ammonium carbonate, 540 (Peppers, 72) INTESTINE. To promote digestion. (Pancreatin, 706) (Diastase, 707) To promote evacuation purgatives. Vegetable purgatives, 93 Saline cathartics, 530 Mercurial purgatives Calo- mel and Metallic prepara- tions, 634 Sulphur, 573 Enemata. Glycerin suppositories, 51 (Atropine). To lessen movement and relax spasm. Opium and Morphine, 206 Tannic acid series, 109 Lime-water, 565 Lead acetate, 670 Bismuth, 692 Atropine (to relax spasm), 276 (Alum, 695) To destroy parasites anthelmintics. Male fern, 116 Pomegranate, 119 Cusso, etc., 118 Santonin, 120 Calomel, 634 Salol, 408 (Some volatile oils). (Chloroform, 178) (Thymol, Naphtol, 400) (Quassia enema, 56) Disinfectants and antiseptics. (Vegetable and Saline purga- tive s). Mercurial purges Calomel, 634 Naphtol, 403 Salol, 408 III. Drugs used for their effects on the circulation. HEART. To strengthen contraction. Digitalis group, 435 To accelerate pulse. Atropine, 276 (Camphor, 426) (Caffeine, 244) To slow the pulse. Digitalis group, 435 Aconite, 328 Veratrine, 334 Strychnine, 195 VESSELS. To contract calibre and raise blood- pressure. Digitalis, 435 Strychnine, 195 Caffeine, 244 Camphor, 426 Ergot, 472 THERAPEUTIC CLASSIFICATION. 731 To relax vessels and lower blood- pressure. Nitrite series, 464 To arrest internal hemorrhage (styptics). Ergot, 472 Hydrastine and Hydrasti- nine, 229 Opium and Morphine (to allay restlessness). To remove fluid (dropsy, anasarca). Digitalis series, 435 Diuretics (see Kidney , be- low). Saline cathartics, 530 Diaphoretics (see Skin, be- low). (Vegetable cathartics, 93) (Salicylic acid, 408) IV. Drugs used for their effects on the genito-urinary system. To increase the flow of urine (diuretics), Caffeine and Theobromine, 244 Digitalis and Squills, 435 (Turpentine, Uva Ursi, Sco- parms). Nitrates, 527 Acetates, 550 Citrates, iodides of the alkalies, 606 Carbonates, 540 Mercury calomel and blue pill, 634 To render the urine less acid. Alkali carbonates and bicarbon- ates, 540 Acetates, 550 Citrates, 550 To render the urine antiseptic. Copaiba series, 74 Salol and Salicylates, 408 Sodium sulphocarbolate, 417 Borax, 578 Urotropin, 425 Local antiseptics, astringents, ano- dynes, caustics, etc., are used in the urethra and bladder. To promote contraction of the uterus (ecbolics). Ergot, 472 Quinine, 353 (Pilocarpine, 311) (Cottonroot-bark, 480) (Hydrastis, 229) To promote menstruation (emmena- gogues). Iron, 655 Vegetable purgatives aloes, 93 (Myrrh). V. Drugs used for their effects on the respiratory system. To stimulate the respiratory centre. Atropine, 276 Caffeine, 244 Camphor, 426 Strychine, 195 (Alcohol ?). To reduce the irritability of the centre in cough. Opium, Morphine, and Codeine, 206 (Heroine). Chloral series, 186 Bromides of the alkalies, 500 To increase and liquefy the bronchial secretion. Ipecacuanha, 339 Tartar emetic, 629 Squills, 435 Senega, 346 Ammonium carbonate, 551 Iodides of the alkalies, 506 (Lobelia, 275) To lessen the secretion of the bronchi (f). Benzoic acid, Benzoin, Tolu Balsam, 419 Ammonium chloride, 496 Cubebs, 73 To relax bronchial spasm (f) in asthma. Belladonna and Atropine, 276 Lobelia, 275 Nitrite series, 464 Iodides, 506 (Charta potassii nitratis, 527) (Aspidosperma, 352) VI. Drugs used for their effects on the central nervous system. Stimulants. (a) The spinal cord. Strychnine, 195 (6) The brain and medulla oblon- gata. Atropine (cocaine), 276 Camphor, 426 Caffeine, 244 Depressants. (a) To paralyze sensation Gen- eral an/Ksthetics. Ether, Chloroform, Nitrous oxide, 153-186 (b) To induce sleep and rest hyp- notics or narcotics. Opium and Morphine, 206 Alcohol, 129 Chloral group, 186 Bromides, 500 Hyoscine, 276 Cannabis indica, 232 732 THERAPEUTIC CLASSIFICATION. To relieve pain analgesics or an Opium, 206 Cannabis, 232 Antipyrine series. 369 (Alcohol, 129) (Chloral, 186) (Arsenic, Iodides, Quinine Nitrites are sometimes of value in headache). VII. Drugs used to reduce fever tern perature. Antipyrine and Acetanilide group 369 Quinine, 353 Aconite, 328 Salicylic acid group, 408 Diaphoretics (see below). (Resorcin, Guaiacol, 401) VIII. Drugs used for their effects on the liver. To increase the secretion of bile chola- gogues. Ox-gall, 708 (Salicylic acid, 408) IX. Drugs used for their effects on the blood. To increase the haemoglobin. Iron, 655 Arsenic, 603 To increase the alkalinity. Alkali carbonate group, 540 Acetates and Citrates, 550 X. Drugs used for specified diseases. In malaria. Quinine, 353 Arsenic, 603 In syphilis. Mercury, 634 Iodides, 506 In rheumatic fever. Salicylates, Salol, 408 In myxoedema and some other thyroid dis- eases. Thyroid extract, 711 In gout. (Colchicum, 343) XI. Drugs used for their effects on the skin. Corrosives or caustics, 729 Emollients and protectives, 729 Local anodynes and anaesthetics, 729 Irritants. Turpentine oil group, 86 Mustard, 88 Cantharides, 89 Croton oil, 97 Tartar emetic,629 Camphor, 426 Menthol, 426 Iodine, 513 Ammonia, 551 (Aconite, 328) (Veratrine, 334) Disinfectant or irritant ointments in parasitic skin diseases. Mercury ointment, 634 Sulphur ointment, 573 Tar, 405 Ichthyol, 407 Benzoin, Storax, and Peru bal- sam, 418 Naphtalin and Naphtol, 403 Resorcin, 401 Thymol, 400 Pyrogallol, 402 Chrysarobin, 102 Camphor, 426 Boracic acid, 578 lodol and other organic iodine compounds, 517 Organic bismuth preparations, 695 Alum preparations, 697 Arsenic, Iodide of Potassium, etc., may be used internally in skin diseases. Drugs administered internally to increase the secretion of perspiration (dia- phoretics or sudorifics). Ipecacuanha, 339 and other nauseating ex- pectorants (antimony). Ipecacuanha and Opium (Do- ver's powder), 339 Camphor, 426 Pilocarpine, 311 Drugs administered internally to lessen secretion of perspiration. Atropine and Belladonna, 276 Agaricin, 297 Camphoric acid, 426 Drugs applied locally and internally to arrest the secretion of milk. Atropine. XII. Drugs used locally for their effects on the eye. Astringents, 729 Disinfectants, 729 Caustics, 729 Anodynes and anaesthetics, 729 Drugs dilating the pupil and relaxing the accommodation mydriatics. Atropine and Homatropine, 276 Cocaine, 298 (Gelseminine, 263) Drugs contracting the pupil and the ciliary muscle myotics. Physostigmine or Eserine, 320 Pilocarpine, 311 (Muscarine, 311) INDEX. The preparations are not mentioned in the index unless when they are met with in the text apart from the chief constituent e. g,, Tinctura digitalis will be found under Digitalis ; but Lead plaster is indexed, because it occurs apart from lead. For metallic salts, see the text under the metal e. g., for Mercury perchloride, see Mercury. A BIES excelsa, 86 A Abrin, 84, 721 Abrus precatorius, 721 Absinthe, 426 Absorption from the alimentary tract, 32 lungs, 32 rectum, 34 skin, 33, 49 subcutaneous tissues, 33 wounds, 34 Acacia, 47 catechu, 113 A. C. E. mixture, 179 Aceta, 40 Acetal, 127 Acetaldehyde, 425 Acetanilide, 369, 380 Acetate of ammonium, 550 Acetates, 549 Acetic acid, 563 ether, 71, 180 Acetone-chloroform, 127 Acetoperacid, 588 Acetophenone, 127 Acetphenetidine, 380 Acetylene, 126 Acid, acetic, 563 agaric, 297 angelic, 334 arabinic, 47 arsenic, 604 arsenious, 604, 616 benzoic, 387, 419 boracic, 578 boric, 578 bromacetic, 127 butyric, 127 cacodylic, 604 caffeotannic, 353 (note) cambogic, 103 camphoric, 298, 426, 431, 433 carbolic, 385, 393, 397 carbonic, 580 cathartinic, 99 cetraric, 59 chavacinic, 72 chloracetic, 127 chromic, 591,699 chrysophanic, 99, 102 Acid, cinnamic, 386, 419, 420 citric, 569 cresotinic, 386, 417 crotonoleic, 98 digallic, 112 ergotinic, 472, 478 filicic, 116 flavaspidic, 116 formic, 563 gallic, 109, 112 gallotannic, 112 gymnemic 302 (note) hydriodic, 510 hydrobromic, 504 hydrochloric, 561 hydrocyanic, 68, 238 hydrofluoric, 521, 562 hydrosulphuric, 575 jalapinic, 103 lactic, 564 lupulinic, 58 meconic, 206 muriatic, 561 nitric, 560 nitrohydrochloric, 561 ophelic, 59 opianic, 229 osmic, 702 oxalic, 564 oxybenzoic, 417 oxynaphtoic, 417 pannic, 116 (note) phosphoric, 562 picramic, 421 picric, 421 piperinic, 72 polygalic, 347 propionic, 125 prussic, 48, 68, 238 pyrogallic, 385, 402 quillaiac, 347 quinic, 353, 549 quinonic, 353 (note) ricinoleic, 98 salicylic, 385, 386, 408 santonin ic, 120 selenic, 702 selenious, 702 sclerotinic, 478 733 734 INDEX. Acid, sozoiodolic, 519 sozolic, 417 sphacelinic, 472 sulfanilic, 512 sulphuric, 560 sulphurous, 562 f tannic, 109 tartaric, 564 telluric, 702 trichloracetic, 563 tropic, 276 valerian ic, 73 Acids, 37, 555 fatty, 563 of the methane series, 127, 563 organic, 563 Acocanthera, 435 Acoines, 311 Aconine, 328, 332 Aconite, comparison with antipyretics, 383 digitalis, 455 Aconitine, 328 Aconitum, 328, 333 Acorin, 70 Action, cumulative, 28 relation between chemical composition and pharmacological, 24 remote, local, indirect, general, 23 Actol, 591 Adeps, 50 lanae, 50 Adhesive plaster, 88, 728 Adipis, oleum, 51 Adjuvants, 28 Administration of drugs, 30 Adonidin, 436 Adonis, 435 Adrenal extract, 459 Adrenalin, 459, 462 ^Ether, 177 aceticus, 180 ^Etheris nitrosi spiritus, 470 ^Ethylis carbamas, 193 chloridum, 177 Affinity, elective, of drugs, 22 Agaric, 297 Agaricin, 297 Agaricus, 297 muscarius, 311 Age in relation to dose, 25 Agropyrum repens, 48 Agrostemma, 347 Ague, brass-founders', 684 Agurine, 251 Airol, 695 Alanin-mercury, 654 Alapurin, 50 Albaspidin, 116 Alcohol, 86, 127, 129 amyl, 144 butyl, 126, 144 food value of, 139 methyl, 144 propyl, 125, 126, 144 Alcohol-chloroform group, 125 Alcoholic preparations, 39 Alcoholism, chronic, 150 Aldehyde, 128 formic, 423 Alkaline earths. See Calcium, Barium, Strontium. carbonates, 540 'hydrates, 540 Alkaloids, 35 Alkasal, 697 Allspice, 67 Almond, 238 , bitter, 67, 238 oil, 51 sweet, 48 Aloe, 101 Aloes, 99 Aloin, 57, 99 Alsol, 697 Althaea, 47 Alum, 624, 695 ammonioferric, 664 Alumen, 697 Aluminium, 695 Alumnol, 697 Amanita, 311 Amidocamphor, 426 Ammonia, 551 Arnmoniacum, 87 Ammonias, substituted, 499 Ammoniated mercury, 650 Ammonium acetate, 550 bases, 499 benzoate, 419 bromide, 504 carbonate, 551 chlorate, 522 chloride, 499 citrate, 553 iodide, 510 salts, 258, 499 Amygdala amara, 67, 238 dulcis, 48 Amygdalae, oleum expressum, 51 Amygdalin, 48, 67, 238 Amyl alcohol, 144 nitrite, 464, 465 Amylamine, 722 Amylene, 126 hydrate, 126, 191, 193 Amylquinine, 258 Amylum, 48 Anacardium, 92 Anacyclus, 72 Anaesthesia, general, 153 infiltration, 307 intraspinal, 308 local, 180, 307 regional, 308 subarachnoid, 308 Anaesthesin, 310 Anaesthetics, general, 153 local action of, 180 mixtures of, 179 preparations of, 177, 180 Anagallis, 707 Analgen, 369 INDEX. 735 Anamirta, 431 Andira araroba, 102 Anemone, 92 Aneson, 127 Anesthol, 179 Anethi fructus, 67 Angostura bark, 59 Anhalonium, 228 Aniline, 35, 369, 424 Animal extracts, 710 soap, 727 Anion, 484 Anise, 67 oil of, 68 Anisol, 386, 400 Anodyne, Hoffman's, 180 Antacids, 545 Antagonistic effects, 29 Anthelmintics, 115 Anthemis, 67 Anthracene purgatives, 99 Anthraquinone, 99 Anthrarobin, 103 Antiarin, 436 Antiaris, 435 Antidote, the arsenic, 666 Antifebrine, 369, 380 Antihydrotics, 298 Antimoniuretted hydrogen, 633 Antimony, 48, 621/629 Antinosin, 519 Antipyretics, 369 Antipyrine, 369, 380 Antiricin, 721 Antiseptic solution, 597 Antiseptics, 385 Antithermine, 369 Antivenin, 721 Antozone, 587 Apalache tea, 244 Aperients, 94 Apocodeine, 107, 236 Apocynin, 436 Apocynum, 435 Apolysine, 370 Apomorphine, 234 Apple seeds, 238 Aqua regia, 561 tofana, 603 Aquse, 38 hydrogen i dioxide, 589 of volatile oils, 70 rosae, unguentum, 50 Aqueous preparations, 38 Arabin, 47 Araroba, 103 Arbutin, 77 Arctostaphylos uva ursi, 77 Argentamine, 691 Argenti cyanidum, 243 Argentic preparations, 690 Argonin, 691 Argyria, 688 Aricine, 353 (note) Aristochine, 364 Aristol, 519 Aristolochia, 57, 59 Aristolochine, 57 Armoracia, 72, 88 Armoracise, spir. co., 69 Arnica, 67, 86 Arnicin, 69 Aromatic bitters, 70 elixir, 69 fluidextract, powder, 71 series, 385 spirit, 70 Arsenate, iron, 667 Arseni iodidum, 617 trioxidum, 616 Arsenic, 603 antidote, 667 Arseniuretted hydrogen, 616 Arsenous acid, 604, 616 Arsine, 616 Artemisia, 120 Asafcetida, 73 Asagrsea, 334 Aseptol, 417 Asiatic pill, 616 Aspidin, 116 Aspidinol, 116 Aspidium, 116 Aspidosamine, 352 Aspidosperma, 352 Aspirin, 386, 414 Asseline, 722 Astragalus, 77 Astringents, metallic, 624 vegetable, 109 Atropa, 277, 291 Atropamine, 277 Atropine, 234, 276, 292 Atroscine, 277 Attar of roses, 68 Aurantii cortex, 67 vinum, 145 Auri chloridum, 698 Azulene, 61 B^EL fruit, 59 Balsam, 37, 419 Canada, 86 copaiba, 76 gurjun, 77 of Peru, 419 traumatic, 419 of Tolu, 419 Balsamodendron, 88 Barbadoes nuts, 97 (note) Barbaloin, 99 Barium, 435, 572 Barley, 48 Barosma, 77 Basham's mixture, 667 Baths, 490 iron and steel, 662 Bearberry, 77 Bebeerine, 59 Bebeeru bark, 59 Bebirine, 59 Beers, 145 736 INDEX. Belladonna, 276, 291 plaster, 728 Belladonnine, 277 Bellatropine, 277 Bengal quince, 59 Benne, oil of, 51 Benzaconine, 328, 332 Benzanilide, 369 Benzene, 385, 392 Benzoates, 418 Benzoic acid, 386, 418 Benzoin, 419 flowers of, 419 Benzoinated lard, 50 Benzol, 385, 392 Benzoperacid, 588 Benzoylecgonine, 298, 306 Benzoylmorphine, 216 Benzoylperoxide, 588 Berberine, 55, 57, 58, 229 Bergamot, oil of, 68 Beryllium, 495 (note), 696 Beta-eucaine, 310 Betol, 386, 412 Betula?, ol. vol., 68, 413 Bhang, 232 Biberine, 59 Bicarbonates, 540, 545 Bichromate, 699 Bile, 96, 708 Birch, oil of, 83, 86, 412 Bismuth, 624, 688 Bitter almonds, oil of, 68, 238 Bitters, 37, 55 aromatic, 70 Bittersweet, 347, 351 Black draught, 101 drop, 219, 220 wash, 653 Blackberry, 113 Blaud's pills, 666 Blazing star, 347 Bleaching powder, 583 Blister, flying, 90, 628 Blistering collodion, 91 Blood, therapeutic use of, 669 Bloodroot, 227 Blue mass ointment, 652 pill, 652 Blumea, 426 Boletus laricis, 297 Bone black, 578 marrow, extract of, 718 Bones, burned, 572 Boracic acid, 578 Bond, 697 Borax, 578 Boric acid, 578 Borneo-camphor, 74, 426 Borneol, 426, 430 Bornylamine, 426 Boroglycerin, 579 Bougies, 31 Brandy, 72, 145 Brassfounders' ague, 684 Brassica, 89 Brayera, 118 Bromacetic acid, 127 Bromal, 191 Bromated camphor, 426, 503 Bromates, 525 Bromelin, 707 Bromides, 500 Bromine, 582 Bromism, 500 Bromoform, 128, 191, 193 Bromol, 397 Bromum, 583 Broom, tops of, 264 Brown mixture, 48, 219 Brown-Sequard's fluid, 718 Brucine, 195, 203 Bryony, 103 Buchheim's classification, 42 Buchu, 77 Buckthorn, 102 Bufonin, 435 (note) Bufotulin, 435 (note) Bunge's theory of iron, 658 Burgundy pitch, 86 plaster, 728 Burnett's solution, 686 Buttonbush, 422 (note) Butyl alcohol, 144 chloral, 127, 190, 193 Butylamine, 722 Butyrates, 550 Butyric acid, 127 Buxine, 55, 58 CACAO, 244, 258 butter, 31, 40, 254, 727 Cachets, 41 Cacodylates, 618 (note) Cacodylic acid, 604 Cactacese, 228 Cactus grandiflorus, 435 (note) Cade, oil of, 405 Cadmium, 701 Caesium, 495 Caffeine, 244 Cajuput, oil of, 68 Calabar bean, 195, 320, 324 Calabarine, 195, 203, 320 Calamus, 70 Calcis, liquor, 570 Calcium, 565 bromide, 504, 572 carbonate, 571 chloride, 570 glycerophosphate, 572 hydrate, 570 hypochlorite, 583 hypophosphite, 530 lactophosphate, 572 peroxide, 589, 590 phosphate, 572 sulphate, 572, 728 sulphide, 575 Calefaciens, emplastrum, 728 Cali nut, 320 Calomel, 651 INDEX. 737 Calumba, 58 Calumbin, 56, 57 Calx, 570 chlorata, 583 sulphurata, 575 Cambogia, 105 Camphor, 426 com. tincture, 220 monobromated, 426, 503 Camphoric acid, 426, 431 Camphorol, 426 Canada balsam, 86 Canadian hemp, 435 moonseed, 59 Canadine, 55, 229 Cane sugar, 54 Cannabin, 232 Cannabinol, 232 Cannabis Indica, 2S2 Canquoin's paste, 686 Cantharidin, 89 Cantharis, 89 Caoutchouc, 728 Capsicum, 72, 93 Capsule, suprarenal, 459 Capsules, 31, 41 Caraway, 67 Carbo, 578 Carbolic acid, 385, 393, 397 Carbon, 578 tetrachloride, 179 Carbonates, 540 Carbonic acid, 580 Carbylamine, 239 Cardamom, 67 Cardol, 92 Carica, 707 Carlsbad salts, 537 Carminatives, 62, 72, 74 Carniferrin, 668 Carolina jasmine, 263 Carragheen, 48 Carron oil, 570 Carum, 67 Caryophyllum, 67 Caryophyllus, 67 Casca bark, 435 Cascara sagrada, 102 Cascarilla, 70 Cassia acutifolia, 101 angustifolia, 101 fistula, 54 purging, 54 Cassise pulpa, 54 Castile soap, 727 Castor oil, 97, 720 Catalase, 588 Cataplasma, 41. See Poultices. Catechu, 112 Cathartics, 94 saline, 530 Cathartin, 99 Cations, 484 Caustic, lunar, 690 mitigated, 690 potash, 545 47 Caustic soda, 545 toughened, 690 Cayenne pepper, 72 Cephseline, 339 Cephalis, 339 Cephalanthin, 422 (note) Cera, 51, 727 Cerates, 30, 40, 727 Ceratum, 51 camphorse, 87 Cerberin, 437 Cerium, 695 Cetaceum, 51 Cetraria, 48 Cetraric acid, 48, 59 Cetrarin, 57 Cevadilla, 334 Cevadilline, 334 Cevadine, 334 Cevine, 334 Chalk, 571 Chalybeate preparations, 664 Chamselirium, 347 Chamomile, 67 Champagne, 146, 580 Charas, 232 Charcoal, 577 Charta, 41 j Chaulmoogra, 93 ! Chavicine, 72 j Chavicinic acid, 72 i Cheiranthin, 437 Cheiranthus, 437 i Chelerythrin, 227 i Chelidonine, 227 i Chelidonium, 227 Chemical composition and action, 24 Chenopodium, 124 Cherry, Virginian, 68, 238 water, 72 Children, dose for, 25 Chili saltpeter, 528 Chillies, 73 Chimaphila, 77 Chinaphenine, 364 Chinotropine, 549 Chirata, 58 Chiretta, 58 Chloracetic acid, 127 Chloral, 127, 186, 192 Chloralamide, 127, 190, 193' Chloralformamide, 190, 193 Chloralose, 127, 191 Chlorates, 522 Chloretone, 127, 191, 193 Chlori, liquor, 583 Chlorides, 486 Chlorinated lime, 583 soda, 583 Chlorine, 582 Chlorodyne, 180 Chloroform, 86, 127, 153, 177 Chlorphenol, 386, 397 Chlorum, 583 Chocolate, 244, 258 Cholagogues, 94, 738 INDEX. Chondrodendron, 59 Chondrus, 48 Christmas rose, 435 Chromic acid, 591, 699 Chromium, 699 Chromotherapeutics, 423 Chrysarobin, 102 Chrysophanic acid, 99, 102 Chrysotoxin, 473 ChuiTus, 232 Cicuta, 432 Cicutoxin, 432 Cinchona, 353 red, 353 (note) Cinchonamine, 353 (note) Cinchonidine, 353 Cinchonine, 353 Cineol, 120 Cinnaldehyde, 71 Cinnamic acid, 386, 419, 420 aldehyde, 71 Cinnamomum camphora, 426 Cinnamon, 67 Cinnamyl-cocaine, 298 Citrates, 550 Citric acid, 564 Citrine ointment, 654 Citrophen, 370 Citrullus colocynthis, 104 Clarets, 145 Classification of drugs, 41 Claviceps purpurea, 472 Cloves, 67 Clysma, 41 Clyster, 41 Coal-tar, 405 Cobalt, 701 Coca, 298, 306 Cocaine, 298, 306 Cocainization, intraspinal, 308 subarachnoid, 308 Cocamine, 298, 305 Coccus, 55 Cochineal, 55 Cochlearia, 73, 88 Cocoa, 244, 258 Codamine, 206 Codeine, 206, 216, 220 Cod-liver oil, 722 Coffee, 244, 252 Coffeon, 252 Cola, 244 Colchicum, 343 Cold, 85 bath, 382 cream, 50, 69 pack, 318 Coleoptera, 89 Colic, painter's, 673 Colica pictonum, 673 saturnina, 673 Collodia, 30, 40, 728 Collodium, 30, 40, 728 cantharidum, 728 flexible, 728 stypticum, 112, 728 Collodium vesicans, 91, 728 Colloid substances, 45 as demulcents, 45 as purgatives, 54 relations of, to salts, 483 Colloxylin, 728 Colocynth, 103 Cologne, eau de, 68 Colophony, 87 Columbo, 55 Commiphora, 88 Common salt, 486 Compresses, hot-water, 85 Concusconine, 353 (note) Condurango, 57, 59 Condy's fluid, 591 Confectiones, 40 Conhydrine, 259 Coniine, 259, 326 Conium, 259 Conjunctiva, applications to, 31 Conquairamidine, 353 (note) Conquairamine, 353 (note) Conquinamine, 353 (note) Conquinine, 353, 362 Convallamarin, 435 Convallaria, 435 Convolvulin, 103 Convolvulus, 105 Copaiba, 74 Copaiva, 74 Copper, 624, 680 arsenite, 604 Coral, 572 Coralline, 572 Coriarnyrtin, 432 Coriander, 67 Coriaria, 432 Corncockle, 347 Cornsilk, 77 Cornsmut, 480 Comutine, 472 Coronilla, 435 Coronillin, 436 Corrosive sublimate, 650 Cotarnine, 229 Goto bark, 58, 59 Cotoin, 58, 59 Cottonroot bark, 480 Cottonseed oil, 51 Couchgrass, 48 Counter-irritation, 78 Court plaster, 728 Cranesbill, 113 Crede's colloid silver, 691 Creolin, 400 Creosols, 386, 407 Creosote, 387, 406 Cresalol, 386, 412 Cresol, 386, 399 Cresotinic acid, 386, 417 Creta, 571 pulv. cum. opio, 220 Crocus, 55 Crotin, 721 Croton-chloral, 127, 190 INDEX. 739 Croton oil, 97 Crotonoleic acid, 97 Croton tiglium, 79, 99, 721 Cruciferse, oils of, 61, 72, 88 Ciyptopine, 206, 218 Cubebin, 74 Cubebs, 74 Cucumber, squirting, 103 Cucurbita, 120 Culver's root, 105 Cumulative effects, 28 Cupratin, 683 Cuprea, 353 Cupric sulphate, 682 Cuprohaemol, 682 Curaoa, 72 Curara, 254, 320 Curarine, 254 Curd soap, 727 Curine, 254 Currier's sumach, 432 Cuscamidine, 353 (note) Cuscamine, 353 ( note ) Cusconidine, 353 (note) Cusconine, 353 (note) Cusparia, 59 Cusso, 118 Cutol, 697 Cuttlefish, 572 Cyanides, 238 Cyanogen, 238 Cyclamen, 347 Cynoctonine, 332 Cypripedium, 67 Cytisus scoparius, 264 PkANDELION, 58 \J Daphne mezereum, 95 Datura, 277, 291 Daturine, 277 Dead tongue, 432 Deadly nightshade, 277 Decocta, 39 Decoctions, 39 Degeneration, fatty, 591, 593 Delirium tremens, 150 Delphinium, 328 Demulcents, 45 Depression, depressants, 20 Derivation, theory of, 78 Dermatol, 694 Dermol, 695 Dextrins, 45 Diacetylperoxide, 588 Diachylon ointment, 50 plaster, 677, 728 Diastase, 707 Didymium, 495 (note) Diethylendiamine, 549 Diffusion, 481 Digallic acid, 112 Digestive ferments, 705 Digitalein, 436 Digitalin, 436 Digitalines, 451 Digitaliresin, 432 Digitalis, 435 comparison with aconite, 333 with antipyretics, 383 Digitonin, 47, 436 Digitophyllin, 436 Digitoxin, 436 Dihydrolutidine, 722 Dill, 67 Dionea, 707 Dionine, 216 Diosphenol, 77 Dioxide of hydrogen, 587 Dipterocarpus-alatus, 76 Discs, 40 Disease, effect of, on dose, 29 Disinfectants, 385 Dissociation of salts, 484 Diterpenes, 61 Diuretin, 251 Dogwood, 422 (note) Donovan's solution, 617, 651 Dorema ammoniacum, 87 Dormiol, 191 Dose, conditions modifying the, 25 Dover's powder, 219, 220, 342 Drastics, 94 Dropwort, water, 432 Drosera, 707 Drugs, 17 action of, 20 chemical character of, 34 classification of, 41 conditions modifying the effect of, 25 definition of, 17 elective affinity of, 22 Dryobalanops, 426 Dryopteris filix-mas, 117 Duboisia Hopwoodii, 266 myoporoides, 277 Duboisine, 277 Dulcamara, 347 Dulcamarine, 347 Dulcin, 55 Dusting-powders, 53 Dyes, aniline, 423 EASTON'S syrup, 363 Eau de cologne, 69, 145 Ecballium, 105 Eccoprotic, 94 Ecgonine, 276, 298, 306^ Effects of drugs, conditions affecting, 25 Effervescing purgatives, 537 Eigon, 516 Elastica, 728 Elaterin, 103 Elaterium, 103, 105 Elderflower, 67 Elective affinity of drugs, 22 Electuaries, 40 Elemi, 88 Elixirs, 39 aromatic, 68 Elm, slippery, 47 Eloeoptene, 61 Embrocations, 40 740 INDEX. Emetics, 237 Emetine, 339 Emodin, 99 Emollients, 49 Emplastra, 30, 41, 727 Emplastrum calefaciens, 91, 728 Emulsa, 39 Emulsin, 48, 67, 238 Emulsions, 32, 39 Endermic, 33 Enema, 31, 41 Epinephrine, 435, 449 Epsom salts, 536 Erbium, 495 (note) Ergochrysin, 473 Ergot, 472 Ergotin, 477 Ericolin, 77 Erigeron, oil of, 68 Errhines, 31 Erythrol tetranitrate, 464, 469 Erythrophoeine, 436 Erytbropbloeum, 435 Erytbroxylon, 306 Eseridine, 320 Eserine, 320 Essences, 71 of volatile oils, 69 Essential oils, 61 Esters, 127 Etber, 71, 126, 153, 177 acetic, 71, 180 nitric, 464 nitrous, 464 Ethereal oils, 61, 86, 387 salts, 127 Etbyl alcohol, 126 bromide, 128, 178 carbamate, 193 chloride, 177, 179, 181 . ether, 127 nitrite, 65, 470 oxide, 177 Ethylene bromide, 178 chloride, 127, 177 Ethylidene chloride, 127, 177 Ethylmorphine, 216 Eucaine, 310 Eucalypti gummi, 113 Eucalyptol, 70, 401 Eucalyptus, 66, 67 oil of, 68, 401 Eudoxine, 519, 695 Eugenol, 71 Eumydrine, 291 Euonymin, 103, 437 Euonymus, 103, 105, 437 Euphorbin, 93 Euphorin, 370 Euquinine, 364 Europhen, 519 Eurotium oryzse, 708 Exalgine, 369, 380 Exodin, 102 Expectorants, nauseating, 237 Extracts, 40 Extracts, animal, 710 fluid, liquid, 39 Extractum aromaticum fluidum, 71 FABTANA, 77 Fats, 49 Fatigue, 255 Fatty degeneration, 591, 593 Fel bovis, 710 Fennel, 67 Ferments, digestive, 705 Ferratin, 668 Ferric preparations, 664 salts. See Iron. Ferrocyanides, 239, 530, 539 Ferrous preparations, 664 Ferruginous preparations, 665 Ferula, 73 galbanum, 87 Ficus, 54 Figs,_54, 707 Filicic acid, 116 Filix mas, 116 Flavaspidic acid, 116 Flavoring substances, 54 Flexible collodion, 728 Flowers of sulphur, 576 Fluorides, 521 Flying blister, 92 Foeniculum, 67 Formaldehyde, 423 Formaline, 423 Formates, 550 Formic acid, 563 Fowler's solution, 617 Foxglove, 435 Frangula, 99, 102 Frangulin, 99 Frankincense, 85 Friar's balsam, 419 Fruit juices, 559 Frumenti, spiritus, 145 Fuller's earth, 53 Fumigation, mercurial, 648 Fusel oil, 144 GADUS, 722 Galbanum, 73, 87 Galipine, 59 Galla, 113 Gallacetophenone, 403 Gallal, 697 Gallic acid, 109, 112 Gambir, 112 Gamboge, 103 Ganja, 232 Garcinia, 105 Gargarisma, 31 Gargle, 31 ^ Gas, laughing, 182 Gaultherise, oleum, 68, 413 Gelatin, 569 capsule, 41 Gelsemine, 195, 202, 263 Gelsemium, 259, 263 General action, 23, 31 INDEX. 741 General anaesthetics, 153 Genitourinary disinfectants, oils used as, 75 Gentian, 58 Geranium, 113 Gigartina, 48 Gila monster, 721 Gin, 72, 145 Ginger, 68, 72 Gland extracts, 711 Glandulae suprarenales, 462 Glauber's salt, 536 Glucose, 54 Glucosi, syrupus, 54 Glucosides, 36 Glusidum, 55 Glycerin, 40, 51 trinitrate, 464, 469 Glycerites, 40 Glyceritum amyl, 51 vitelli, 51 Glycerophosphates, 539 Glycerylis nitras, 470 Glycol, 126 Gly cos ides, 36 Glycyrrhiza, 48 Glycyrrhizin, 48 Gnoscopine, 206 Goa powder, 102 Gold, 698 Golden seal, 229 Gonolobus, 59 Gorite, 589 Gossypii, radicis cortex, 480 seminis, ol., 51 Goulard's extract, cerate, lotion, 677 Granatum, 19 Grape cure, 59 Gray oil, 653 powder, 652 Greens, Scheele's, Schweinfurt's, Paris, 604 Gregory's powder, 100 Grey oil, 653 powder, 652 Griffith's mixture, 666 Guaiacol, 386, 407 carbonate, 386, 407 salol, 412 Guaiacum, 87 Guarana, 244, 251 Gum, 37, 45 arabic, 47 Gum-resins, 37 Gun-cotton, 728 Gurjun balsam, 76 Gymnema silvestre, 302 (note) Gymnemic acid, 302 (note) Gynocardia, 93 Gypsophila, 347 Gypsum, 572, 728 TT7EMATOGEN, 668 11 Haematoxylon, 113 Hsemogallol, 669 Hemoglobin, 669 Hjemol, 669 Hagenia, 18 Hamamelis, 113 Hard soap, 727 Hamack's experiment, 323 Hartshorn, spirit of, 552 Hashish, 232 Heat, 86 Heavy metals, 621 Hedeoma, 67 Hedonal, 127, 191, 193 Hellebore, green, white, 334 Helleborein, 436 Helleborus niger, 435 Heloderma, 721 Hemidesmus, 351 Hemlock, 259 water, 432 Hemp, Canadian, 435, 452 Indian, 232 Henbane, 277 Hepar sulphuris, 575 Hesperidin, 69 Heteroxanthine, 244 Henamethylenamine, 425 Hexylamine, 722 Hock, 145 Hoffmann's anodyne, 180 Holocaine, 311 Homatropine, 277, 290 Homococamine, 298 Homochelidonine, 227 Homocinchonidine, 353 (note) Homoisococamme, 299 Honey, 39, 54 Hops, 58 Hordeum, 48 Horehound, 67 Horseradish, 69, 72 Hot compresses, 86 Humulus, 59 Hunyadi-janos, 537 Hydragogues, 94 Hydrargyrum, 640 Hydrastine, 229, 230 Hydrastinine, 229, 230 Hydrastis, 229 Hydrates, 540 Hydriodic acid, 510 Hydrobromic acid, 504 Hydrochloric acid, 561 Hydrocinchonine, 353 (note) Hydrocotarnine, 206, 217 Hydrocyanic acid, 238 Hydrofluoric acid, 521,562 Hydrogen, antimoniuretted, 633 arseniuretted, 616 dioxide, 587 ion, 555 peroxide, 587 phosphuretted, 592 sulphuretted, 575 Hydroquinidine, 353 (note) Hydroquinine, 353 (note) Hydroquinone, 77, 385 Hydrosulphuric acid, 575 742 INDEX. Hygrine, 299 (note) Hyoscine, 276, 289, 292 Hyoscyamine, 276, 288, 292 Hyoscyamus, 277, 291 Hypertonic solutions, 482 Hypnal, 192, 369 Hypnone, 127, 192 Hypnotics, 186 Hypochlorites, 583 Hypodermic injection, 33 Hypophosphites, 530 Hypophysis, extract of, 718 Hypoquebrachine, 352 Hyposulphites, 529 Hypotonic solution, 482 ICELAND moss, 48, 59 1 Icythyocolla, 728 Ichthyol, 387, 407 Idiosyncrasies, 27 Ignatia, 195 Ilex, Paraguay, 244 Immunity, 28, 720 India-rubber, 728 Indian corn, 78 hemp, 232 tobacco, 275 Indirect action, 23 Infiltration anaesthesia, 307 fatty, 592 Infundibular body, 718 Infusa, 39 \ Infusions, 39 Ingluvin, 707 Injection, hypodermic, 33 intravenous, 34 subcutaneous, 33 Insect poisons, 721 Internal secretions, 710 Intestine, absorption from, 32 Intraspinal cocainization, 308 Intravenous injection, 34 Inunction, 33, 646, 653 lodalbumin, 716 lodates, 525 Iodides, 506 Iodine, 513 lodipin, 516 lodism, 506, 514 lodoform, 517 lodol, 519 lodolen, 516 lodolum, 520 lodospongin, 716 lodothyrin, 711 lodum, 515 Ions, 484 Ipecacuanha, 339 Ipecacuanha pulvis co., 220 cum scilla, pil., 220 Ipomo3a, 105 Irish moss, 48 Iron, 624, 655 arsenate, 617 hypophosphite, 530 Irritants, 20 Irritants, skin, 78 Irritation, 20 Isinglass, 728 Isoamyl alcohol, tertiary, 126 Isobutyl nitrite, 468 Isococamine, 298 Isolichenin, 48 Isonitriles, 239 Isopelletierine, 119 Isopilocarpine, 311 Isopral, 192 Isopunicine, 119 Isoquinoline, 35, 262 Isotonic solutions, 482 Itrol, 691 Ivy poison, 92 TABOEANDI, 311, 317 d Jaborine, 311 (note) Jalapa, 105 Jalapin, 103 Jarnbul, 725 James' powder, 633^ Japaconitine, 328 Jasmine, yellow or Carolina, 263 Jateorhiza, 58 Jatropha, 97 (note) Javelje's solution, 583 Jecoris aselli, oleum, 724 Jequirity, 721 Jervine, 334, 339 Jesuit's drops, 419 Juices, 40 Juniper, empyreumatic oil of, 405 oil, 68 sabina, 86 tar oil, 405 KAIEINE, 369 Kairoline, 369 Kali nut, 320 Kamala, 120 Kaolinum, 53, 727 Ration, 484 Kava-kava, 73 Kelene, 179 Keratin, 727 Kermes mineral, 633 Ketones, 127 Kino, 113 pulvis comp., 220 Kirschwasser, 72 Kola, 244 Kombe, 435 Kosotoxin, 118 Kousso, 118 Krameria, 112 Kresamine, 400 Kryofine, 370 Kummel, 72 T ABAEEAQUE'S solution, 583 L Lactates, 550 Lactation, medication during, 26 Lactic acid, 564 Lactophenine, 370, 380 INDEX. 743 Lactophosphate, 572 Lactose, 54 Lactuca, 234 Lactucariurn, 234 Lady's slipper, 67 Lamella-, 40 Lanichol, 50 Lanolin, 50 Lanthanum, 495 (note) Lanthopine, 206 Lappaconitine, 332 Lard, 50 oil of, 51 Largin, 691 Larynx, application to, 31 Laudanine, 206, 217 Laudanosine, 206 Laudanum, 219, 220 Laughing gas, 182 Laurel, 67, 238 camphor, 429 leaves, 67, 238 water, 69 Laurocerasi folia, 67, 70 Laurocerasus, 238 Lavender, oil of, 68 Laxative, 94 Lead, 624, 670 iodide, 51 palsy and arsenic, 607 plaster, 728 Lemon, 67 essential salts of, 564 juice, 564 oil of, 68 Leptandra, 105 Leptandrin, 103 Lettuce, 234 Levant wormseed, 122 Levico water, 617 Lichenin, 48 Lily of the valley, 435 Lime, 564, 570 chlorinated, 583 hypophosphite, 530 juice, 564 phosphate, carbonate, 53 sulphurated, 575 Limonis cortex, 67 Lini oleum, 51 Liniments, 40 Linimentum camphorae, 86 chloroformi, 86, 180 saponis, 86 Linseed, 47 . oil, 51 Linum, 47 Lipanin, 723 Liqueurs, 67, 71 Liquidambar, 419 Liquidextracts, 39 Liquor antisepticus, 579 epispasticus, 91 hydrogenii dioxide, 589 Liquores, 39 Liquorice, 48 Litharge, 677 Lithium, 495 benzoate, 419 bicarbonate, 545 bromide, 504 carbonate, 545 citrate, 536 hydrate, 545 salicylate, 413 Liver of sulphur, 575 Lizard, poisonous, 721 Lobelia, 275 Lobeline, 266, 275 Local action, 23 anaesthesia, 180, 307 Logwood, 113 Loretin, 519 Losophan, 579 Lotions, 39, 653 Lozenges, 31, 40 Lugol's solution, 515 Lunar caustics, 690 Lungs, absorption from, 32 administration by, 30 Lupine, 264 (note) Lupinine, 264 (note) Lupulin, 58 Lupulinic acid, 57 Lupulus, 58 Lycaconitine, 333 Lycetol, 549 Lycopodium, 53 Lysidine, 549 Lysol, 400 Lytta, 89 MACE, 68 Magisterium bismuthi, 693 Magnesia, 536 fluid, 536 Magnesium, 535 carbonate, 536 chloride, 530 citrate, 530 oxide, 530 peroxide, 590 salts, 535 sulphate, 536 Maize, 78 fungus of, 480 Malakine, 370, 380, 412 Malates, 530 Male fern, 116 _ Mallotus, 120 Malonates, 554 Malt, 54 enzyme, 707 extract, 707 Maltine, 707 Maltzyme, 707 Mandragora, 277 Mandragorine, 277 Mandrake, 277 Manganese, 700 Mangani dioxidum, 700 Manicheel tree, 93 744 INDEX. Maunitol hcxanitrate, 464 Marrubium, 07 MarahmaJlow, 47 Massa, 40 Mastiehe, 102 Mate, 244 Materia mediea, definition of, 19 Matieo, 7(5 Matriearia, 67 Maydis ustilago, 480 Meals, influence of, on dose, 26 Meeonie acid, 206 Meconidine, 206 Medicated waters, 38 Medication. local, 30 Mel, 54 Mellita, 39 Menispermurn, 55 eoceulus, 431 Menstruation, 26 Mentha, 67 Menthane, 426 Menthol, 71, 42M29, 728 Mereurialisin, 637 Meivury, 621-628, 634 iodide, 510, 651 sozoiodolate, 519, 654 Mesotan, 416 (note) Metaeresol, 399 Metadinitrobenzol, 421 Metals, heavy, 621 minor, 698 Metaphosphates, 535 Methaeetine, 370 Methyl alcohol, 144 bromide, 179 chloride, 181 coniine, 259 hydroOjiiinone, 77 morphine, 216 salieylate, 68, 386, 412 strychnine, 258 Methyl-arbutin, 77 Methylal, 127 MethyJamine, 499 Methylatropine, 291 Methylene bichloride, 178 bine, 423 Methylis salicylas, 413 Methylthionin, 423 Meyer-Overton theory of narcosis, 20, 127, 166 Mezeal button, 228 Mezcaline, 228 Mezereum, 92, 93 Milk of lime, 571 sugar of, 54 of sulphur, 576 Mindererns, spirit of, 553 Mineral waters, 576, 582, 668 alkaline, 547 iron, 666 Mint, essence of, 72 Mist une, 39 Mithridatism, 27 Mitigated caustic, 690 Mixture, 39 brown, 48 Molasses, 54 Molybdenum, 701 Monkshood, 328, 333 Monobromated camphor, 426, 503 Monoehlorphenol, 386, 397 M ousel's solution, 665 Moonseed, Canadian, 59 Morphine, 206, 218 comparison with antipyrine, 383 poisoning, atropine in, 295 Morphinism, 225 Morpholine, 206 Morrhwe, oleum, 724 Morrhuine, 722 Morrhnol, 723 Mosehus, 431 Mouth, administration by, 30, 31 Muawine, 437 Mucilages, 39, 47 Mucuna, 320 Muriatic acid, 561 Muscale buttons, 228 Muscarine, 311,326 Mushrooms, 311 Musk, 74, 431 Mustard, 72, 88 Myoctonine, 333 Myristica, 67 Myronate, 88 Myrosin, 88 Myroxylon, 419 Myrrha, 88, 102 \TAPHTHALAN, 387 ll Naphthalene, 385, 402 Naphtalol, 412 Naphthylamine, 421 Naphtol, 385, 403 Narceine, 206, 217 Narcosis, Mayer-Overton theory of, 20, 127, 166 Narcotics of methane series, 126, 186 Narcotine, 206, 217, 229 Nectandne cortex, 59 Neriin, 436 Neriodorin, 436 Nerinm, 435 Neroli, oil of, 68 Neurodine, 370, 380 Neuronal, 193 Newt, 432 Ngai-camphor, 426 Nickel, 701 Nicotiana, 266, 273 Nicotin, 266, 326 Nightshade, black, 347 deadly, 277 Nitrates, 464, 527 Nitre, 528 sweet spirits of, 469 Nitric acid, 560 ethers, 464 Nitriles, 239 Nitrites, 464 INDEX. 745 Xitrobenzol, 420 Nitro-bodies, 464 Nitroethane, 464 Nitroglycerin, 464, 469 and digitalis, 456 Nitrohydrochloric acid, 561 Nitromethane, 464 Nitrous ether, 464 oxide, 182 Nose, application to, 31 Nosophen, 519 Nut-gall, 113 Nutmeg, 67 Nuts, Barbadoes, 97 (note) purging, 97 (note) Nux vomica, 195 OAK BARK, white, 113 poison, 92 Octane, 126 (Enanthic ethers, 72, 129, 145 CEnanthotoxin, 432 (Enanthylates, 550 Oil. See Oleum. cod-liver, 722 cotton-seed, 51 fusel, 144 of roses, 67 Oils, 49, 51 essential, 61 ethereal, 61 purgative, 97 volatile, 61 Ointments, 30, 40, 50 Olea, 51 Oleander, 435 Oleandresin, 432 Oleandrin, 436 Oleates, 40 Oleites, 351 Oleoresin zingiberis, 68 Oleoresins, 37 Oleum adipis, 51 amygdalae amarae, 67, 238 expressum, 51 anethi, 68 anisi, 68 aurantii florum, 68 bergamottae, 68 betulae, volatile, 68, 412 cadinum, 405 cajuputi, 68 carui, 68 caryophylli, 68 chenopodii, 124 cinereum, 653 cinnamomi, 68 copaibae, 76 coriandri, 68 crotonis, 97 cubebae, 76 erigerontis, 68 eucalypti, 68 foeniculi, 68 gaultheriae, 68, 412 gossypii seminis, 51 Oleum hedeomae, 68 jecoris aselli, 724 juniperi, 68, 86 lavandulae florum, 68 limonis, 68 lini, 51 menthse piperitae, 68 viridis, 68 morrhuae, 724 myrciae, 68 myristicae, 68 olivae, 51 phosphoratum, 601 picis, 405 pimentae, 68 pini, 86 ricini, 97 rosae, 68 rosrnarini, 68 sabinae, 68, 86 santali, 76 sassafras, 68 sinapis, volatile, 89 terebinthinfe, 86 theobromatis, 727 thymi, 68 tiglii, 97 Olive oil, 46, 51, 723 Oophorin, 719 Ophelic acid, 58 Opianic acid, 229 Opium, 206 Orange flowers, oil of, 68 peel, 67 wine, 145 Ordeal bean, 320, 324 Orexine, 59 Organic acids, 563 iron, 655 Organotherapeutics, 710 Orphol, 695 Orpiment, 603 Orthocresol, 399 Orthoform, 310 Orthophosphates, 535 Oscine, 276 Osmic acid, 702 Osmosis, 482 Osmotic pressure, 482 Otto of roses, 68 Ouabaio, 435 Ourouparia, 112 Oxalates, 553 Oxalic acid, 564 Oxgall, 710 Oxybenzoic acid, 417 Oxygen, 585 Oxymel, 39, 54 Oxynaphtoic acid, 386, 417 Oxynarcotine, 206 Ozone, 586 PACK, hot, cold, 318 Palmitates, 550 Palsy, painters', 673 Panama bark, 351 746 INDEX. Pancreas, extract of, 718 Pancreatic ferment, 706 Pancreatin, 706 Pannic acid, 116 (note) Papain, 707 Papaja, 707 Papaveramine, 206 Papaverine, 206, 217 Papaveris capsulae, 220 Papaver rhoeas, 55 somniferum, 206 Papayotin, 707 Papers, 41 Papoid, 707 Paracotoine, 58 Paracresol, 399 Paraffin, 50 Paraform, 424 Paraguay tea, 244 Paraldehyde, 127, 189, 192 Paralysis, definition of, 21 and fatigue, relation between, 255 Paramidophenol, 370 Paraxanthine, 244, 252 Paregoric, 219, 429 Pareira, 59 Parilla, yellow, 59 Parillin, 347 Paris green, 604 plaster of, 572, 728 Pathological conditions modifying dose, Paullinia, 244 Pawpaw, 707 Payta, 352 Paytanine, 352 Pearson's solution, 616 Pelletierine, 119 Pellitory, 72 Pellote, 228 Pennyroyal, 67 oil, 67 Pental, 126, 178 Pentane, 126 Pepo, 120 Pepper, 72, 93 black, 72 Cayenne, 72 Peppermint, 67 oil of, 68 Pepsin, 705 Pepsinum, 705 Peracids, 588 Perchlorates, 525 Perchlorethane, 179 Permanganates, 589 Peronine 216 Peroxide of hydrogen, 587 Peroxides, 589 Persodine, 589 Persulphates, 589 Peru, balsam of, 419 Petrolate, 50 Petroleum, 50 Peyotl, 228 Pharmacognosy, 19 Pharmacological action and chemical struct- ure, 24 Pharmacology, definition of, and relations to biology and clinical subjects, 17-19 Pharmacopeia, 37 Pharmacy, 19 Pheasant's eye, 435 Phenacetine, 370, 380 Phenanthren, 206 Phenazone, 380 Phenetidines, 370 Phenetol, 386 Phenocoll, 370, 380 Phenol, 385, 393, 397 Phenylhydrazine, 369 Phenylis salicylas, 414 Phloretin, 725 Phloridzin, 725 Phosphates, 535 Phosphidum zinci, 601 Phosphine, 601 Phosphorated oil, 601 Phosphoric acid, 562 Phosphorus, 591, 601 sesquisulphide, 593 (note) Phosphuretted hydrogen, 592 Physostigma, 320, 324 Physostigmin, 320, 324 Phytolacca, 434 Phytolaccatoxin, 432 Pichi, 77 Picis liquidae, oleum, 405 emplastrum cantharidatum, 91, 728 Picrsena, 58 Picric acid, 421 Picroaconitine, 328 Picropodophyllin, 103 Picrotin, 431 Picrotoxin, 431 Pills, 40 cathartic vegetable, 105 compound cathartic, 105 Pilocarpidine, 311 (note) Pilocarpine, 311, 326 Pilocarpus, 311 Pilulse, 40 cathartic vegetable, 105 composite, 105 Pimenta, 67 Pimpernel, scarlet, 707 Pimpinella, 67 Pineapple, 707 Pink-root, 123 Pinus, 86, 405 Piper, 72 angustifolium, 76 cubeba, 75 Piperazine, 549 Piperidine, 72, 259, 262 Piperine, 72 Pipirinic acid, 72 Pipsissewa, 77 Pitch, Burgundy, 86, 728 plaster, 86, 728 Pituitary gland, 718 Pituri, 266 INDEX. 747 Piturin, 266 Fix Burgundica, 86 carbonis and liquida, 405 Plasters, 30, 41, 727 warming, 91 Platinum, 698 Plum stones, 238 ^ Plumbi suppositpria, co , 220 cum opio, pilula, 220 Plumbum, 670 Plummets pills, 633 Podophyllotoxin, 103 Podophyllum, 103, 105 Poison ivy and oak, 92 Poisons, 17 Pokeberry, 432 Pokeroot, 435 Polygala, 347 Polygalic acid, 347 Polysolve, 351 Pomegranate, 119 Poplar, 413 Poppy, red, 55 Port wine, 145 Potash, 540, 545 water, 582 Potassa, 545 sulphurata, 575 Potassium acetate, 550 action of, 494 arsenite, 617 bicarbonate, 545 bichromate, 699 bitartrate, 536 bromide, 500 carbonate, 545 chlorate, 522 chloride, 494 citrate, 531, 536 dichromate, 699 ferrocyanide, 539 hydrate, 545 hydroxidum, 545 hypophosphite, 530 iodate, 525 iodide, 506 lactate, 550 malate, 531 nitrate, 528 nitrite, 464, 469 oxalate, 553 perchl orate, 525 permanganate, 589 persulphate, 589 phosphate, 531 propionate, 550 relation of, to lime, 568 salts, 494 sozoiodolate, 519 sulphate, 535 sulphide, 575 tartrate, 531 thiosulphate, 530 valerianate, 550 Potato, 347 Poultices, 41, 85 Powders, 40 bleaching, 583 dusting-, 53 Seidlitz, 537 Precipitate, white, 653 Pregnancy, 26 Preparations, alcoholic, 39 aqueous, 38 pharmacopceial, 37 Propionates, 550 Propyl alcohol, 126, 144 nitrite, 464 Protargol, 691 Protocurarine, 254 Protocuridine, 254 Protocurine, 254 Protopine, 206, 218, 227 Protoplasm poisons, 22 Protoveratridine, 334, 337 Protoveratrine, 334, 337 Prune stones, 238 Prunes, 54 Prunus amygdala, 48 laurocerasus, 238 Virginiana, 67, 238 Prussic acid, 48, 68, 238 Pseudaconitine, 328 Pseudohyoscyamine, 277, 290 Pseudojervine, 334 Pseudomorphine, 206 Pseudostrophanthin, 436 Psychotria, 342 Pterocarpi lignum, 55 Pterocarpus, 113 Ptomatropine, 278 Pulsatilla, 92 Pulveres, 40 Pulvis, aromatic, 71 effervescens co., 537 Pumpkin seed, 120 Punica, 119 Punicine, 119 Purine bodies, 244 Purgatives, 93, 102 anthracene, 98 effervescing, 537 oily, 97 saline, 530 vegetable, 93 Purging nuts, 97 (note) Pustulants, 78 Pyoctanine, 423 Pyrethric acid, 72 Pyrethrum, 72 Pyridine, 35, 259, 262 Pyrocatechin, 385, 396 Pyrodine, 369 Pyrogallol, 385, 402 Pyrophosphates, 535 Pyrovanadates, 701 Pyroxylin, 728 rvUAIKAMIDINE, 353 (note) \J Quairamine, 353 (note) Quassia, 58, 116 Quassiin, 55, 57, 58 748 INDEX. Quebracho, 352 Quercus, 113 Quicksilver, 634 Quillaja, 347 Quinamine, 353 (note) Quince, Bengal, 59 seeds, 48 Quinetum, 364 Quinidine, 353, 362 Quinic acid, 549 Quinine, 353 compared with antipyretics, 383 hydrobromate, 504 tasteless, 364 Quinoidine, 364 Quinoline, 35, 259, 262, 369 Quinova red, 353 (note) Quinovin, 353 (note) RASPBEEEY, 54 Kealgar, 603 Eectified spirits, 145 Eectum, application to, 31, 34, 40 Kegional anaesthesia, 308 Eemijia, 353 Eemote action, 23 Eesin, 87, 728 Eesinous purges, 103 Eesins, 36 Eesopyrin, 69 Eesorcin, 385, 401 Eesorcinol, 401 Eevulsion, theory of, 78 Ehamnus purshiana, 102 Ehatany, 112 Eheum, 100 Ehoeadine, 206 Ehoeados petala, 55 Ehubarb, 99 Ehus glabra, 113 radicans, 93 toxicodendron, 92 Eicin, 98, 720 Eicinus, 98, 99, 720 Eoburite, 421 Eochelle salt, 536 Eosa, 67 Eose petals, 67 Christmas, 435 Eosemary, oil of, 68 Eoses, attar, otto, oil of, 68 Eosmarinse, oleum, 68 Eottlerin, 120 Eubefacients, 78 Eubidium, 495 Eubijervine, 334 Eubus, 113 idseus, 54 Eum, 72, 145 CJABADILLA, 334, 339 kJ Sabadine, 334, 339 Sabina, 67, 86 Saccharides, 36 Saccharin, 55 Saccharum, 54 Saccharum lactis, 54 Saffron, 55 Safrol, 71 Sage, 65, 67 Salamander, alkaloids of, 36 Salep, 48 Salicin, 413 Salicylates, 385, 386, 408 Salicylic acid, 76 (note), 385, 386, 408 Saline cathartics, 530 Saliphen, 370, 380, 412 Salipyrine, 369 Salithymol, 386 Salol, 386, 412 Salophen, 370 Salt action, 481 common, 486 of sorrel, 564 Saltpetre, 528 Salts, 481 dissociation of, 484 ethereal, 127- purgative, 530 smelling, 552 Salumin, 697 Salves, 30, 40 Salvia, 67 Sal volatile, spirit of, 552 Samandarine, 432 Sambucus, 67 Sandalwood, 74 oil of, 74 red, 55 Sanders, 55 Sanguinaria, 227 Sanguinarine, 227 Santalol, 74 Santalum album, 76 rubrum, 55 Santonica, 122 Santonin, 120 Santoninoxim, 122 Sapo, 86, 727 Saponaria, 347 Saponin, 346 Saporubrin. 347 Sapotoxin, 346 Sarsse radix, 351 Sarsaparilla, 347 Sarsaponin, 347 Sassafras, 47, 67 Sassy bark, 435 Saturnine colic, palsy, 673 Saunders, 55 Savine, 65, 68, 86 Scammony, 103 Schsenocaulon, 334 Scheele's green, 604 Schleich's infiltration anaesthesia, 307 mixtures, 179 Schmiedeberg's classification, 42 Schweinfurth's green, 604 Scilla, 435 pil. ipecac, cum, 220 Scillain, 436 Scillotoxin, 452 INDEX. 749 Sclerotinic acid, 472 Seoparin, 264 Scopolamine, 276, 289, 292 Scopoleine, 277, 291 Scopolia, 277, 291 atropoides, 277, 291 Scopoline. 276 Scorpion, 721 Scurvy grass, 73 Secale, 472 Secaline, 473 Secalintoxin, 473 Secretions, internal, 710 Securite, 421 Sedine, 72 Sedum acre, 72 Seidlitz powder, 537 Selenium, 702 Semecarpus, 92 Senega, 347, 351 Senegin, 347 Senna, 99, 101, 102 Sepia, 572 Septentrionaline, 332 Serpentaria, 59 Serpentary, 57 Sesame oil, 51 Sesquiterpenes, 61, 75 Sevum, 50 Sex, influence of, on dose, 26 Sherry wine, 145 Sidonal, 549 Silver, 624, 686 colloid, 691 nitrate, 686 Sinalbin, 88 Sinapis, 88 Sinigrin, 88 Size, influence of, on dose, 25 Skin, application of drugs to, 30, 33 irritants, 78 Slippery elm, 47 Smilacin, 347 Smilax, 347, 351 Snake poison, 721 root, 59 Soap, 86, 220, 727 bark, 347, 351 curd, 727 hard, 727 soft, 727 Soaps, compound pill of, 220 Soapwort, 347 Socaloin, 99 Socatrine aloes, 101 Soda, 545 chlorinated, 583 water, 580 Sodse chloratse, liquor, 583 Sodium acetate, 550 arsenate, 617 benzoate, 419 bicarbonate, 545 bisulphite, 530 borate, 579 bromate, 525 Sodium bromide, 500 butyrate, 550 cacodylate, 618 (note) caprylate, 550 carbonate, 545 chlorate, 522 chloride, 486 citrate, 536 citrotartrate, 536 ethylate, 545 ferrocyanide, 531 fluoride, 521 fluorosilicate, 522 formate, 550 hydrate, 545 hydroxide, 545 hypophospite, 530 hyposulphite, 530 iodate, 525 iodide, 506 lactate, 550 malate, 531' malonate, 554 metacresotinate, 417 nitrate, 528 nitrite, 464, 469 cenanthylate, 550 orthocresotinate, 417 oxalate, 553 palmitate, 550 paracresotinate, 417 perchlorate, 525 persulphate, 589 phenolsulphonas, 417 phosphate, 536 proprionate, 550 pyrophosphate, 536 salicylate, 386, 408, 413 silicate, 728 sozoiodolate, 519 stearate, 550 succinate, 554 sulphate, 531, 536 sulphide, 573 sulphite, 530 sulphocarbolate, 386, 417 sulphovinate, 537 tartrate, 531, 536 thiosulphate, 530 valerianate, 550 Soft soap, 727 Solanacese, alkaloids, 277 Solanein, 347 Solanine, 346, 347 Solanidine, 347 Solanum, 347 Solutions, 481 antiseptic, 579 Solutol, 400 Solveol, 400 Solvines, 351 Soporifics, 186 Sorrel, salts of, 564 Sowbread, 347 Sozoiodolates, 519 Sozolic acid, 417 750 INDEX. Spanish fly, 89 Sparteine, 259, 264 Spartium, 264 Spearmint, 67 oil of, 68 Spermaceti, 51 Spermine, 719 Sphacelinic acid, 472 Sphacelotoxin, 473 Spider poison, 721 Spigelia, 123 Spirits, 71, 145 Spiritus, 39 frumenti, 145 rectificatus, 145 vini gallici, 145 of volatile oils, 69 Spleen, extract of, 718 Spruce fir, Norway, 86 Squills, 435 Squirting cucumber, 103 Stannous salts, 701 Staphisagria, 328, 333 Star anise, 67 blazing, 347 Starch, 45, 48, 51, 53 glycerite, 51 Stavesacre, 328, 333 Stearates, 550 i Stearoptenes, 61, 426 Stupe, turpentine, 87 Sterculia, 244 Sternutatories, 31 St. Ignatius' bean, 203 Stibine, 633 Stimulation, 20 Stomach and intestine, absorption from, 32 administration by, 30 Stonecrop, biting, 72 Storax, 419 Stramonium, 277, 29] Strontium, 572 bromide, 504 iodide, 510 lactate, 550 salicylate, 413 Strophanthus, 435, 451 Structure, chemical and pharmacological action of, 24 Strychnine, 195, 203, 218 comparison with atropine and caffeine, 279 with digitalis, 455 with picrotoxin, 433 Strychnos, 195, 203, 254 Styptic collodion, 112, 728 Stypticine, 231 Styrax, 419 Subarachnoid cocainization, 308 Subcutaneous injection, 33 Sublimate, corrosive, 650 Succi, 40 Succinates, 554 Suet, 50 Sugar, 45, 54 Sugar of lead, 670 Sulphanilic acid, 512 Sulphates, 535 Sulphides, 573 Sulphites, 529 Sulphocarbolates, 386, 417, 685, 695 Sulphonal, 127, 189, 192 Sulphonmethanum, 192 Sulphonmethylmethanum, 192 Sulphovinate, 537 Sulphur, 573 flowers of, 576 iodide, 516 milk of, 576 sublimated, 576 washed, 576 Sulphuretted hydrogen, 575 Sulphuric acid, 560 ether, 177 Sulphuris, hepar, 575 Sulphurous acid, 562 Sumach, 113 Currier's, 432 Sumbul, 73 Sundew, 707 Suppositories, 40 Suppository, 31 glycerin, 52 Suprarenal capsule, extract of, 459 Suprarennin, 459 Swamp dogwood, 422 (note) Swertia chirata, 58 Synergists, 28 Syrupus, 39, 54 aromaticus, 70 Systemic action, 23 Syzygium, 725 rp A BELIZE, 40 1 Tablet triturates, 40 Taka-diastase, 708 Talc, 53 Tamarind, 54 Tanacetum, 68 Tanghinia, 437 Tanghinin, 437 Tannal, 697 Tannalbin, 113 Tannic acid, 109 Tannigen, 113 Tannocol, 114 Tannoform, 113 Tannopin, 113 Tansy, 68, 115 Tar, 386, 405 Tarantula, 721 Taraxacum, 58 Tartar, cream of, 535 emetic, 79, 629 Tartaric acid, 559, 564 Tartrates, 531 Tea, 244, 252 Teel oil, 51 Tellurates, 702 Tellurium, 702 Terebene, 86 INDEX. 751 Terebinthina, 85 Terpenes, 61, 86 Terpin hydrate, 86 Testicle, extract of, 718 Tetrachloride of carbon, 179 Tetraiodpyrrol, 519 Tetronal, 127, 191. 193 Thalline, 369, 380 Thallium, 701 Thea, 244 Thebaine, 195, 203, 206,217 Theine, 244 (note) Theobroma, 244 Theobromine, 244 Theocine, 244 Theon, 253 Theophylline, 244 Therapeutics, 17 Thermifugine, 369 Thermodine, 370, 380 Thevetia, 435 Thevetin, 436 Thilanin, 576 Thioform, 695 Thiol, 387, 407 Thiosinamine, 577 Thiosulphates, 530 Thornapple, 277 Thujon, 426 Thus Americanum, 85 Thyme, 66, 400 Thymol, 66, 385, 400 Thymolis iodidum, 520 Thymosalol, 412 Thymus extract, 718 Thyreoglobulin, 711 Thyreoiodin, 711 (note) Thyroid extract, 711 Thyroidism, 715 Tin, 624, 701 Tinctures, 39 Tobacco, 266, 274, 281 Indian, 266, 275 Tolerance, 27, 720 Tolu, balsam of, 419 Toluifera, 419 Toluol, 385, 392 Tolutana tinctura, 419 Toluylendiamine, 422 Toot poison, 432 Toughened caustic, 690 Toxalbumin, 98, 720 Toxicodendrol, 92 Toxicology, 17 Toxiresin," 432 Tragacanth, 47 Tribromphenol, 397 Trichloracetic acid, 563 Trichlorphenol, 386 Tricresol, 400 Triiodocresol, 519 Trimethyl-ammonium, 312, 499 Trimethylamine, 126, 722 Trinitrate of glycerin, 464 Trinitrini, liquor, 470 Trional, 127, 191, 193 Trioxybenzol, 402 Triticum, 48 Tritopine, 206 Trituratio, 40, 105 Trituration, 40 Troches, 40 Trochisci, 31, 40 Tropacocaine, 299, 306 Tropeines, 277, 290 Tropic acid, 276 Tropine, 276 Tubocurarine, 254 Tully's powder, 220 Tumenol, 387 Tungsten, 701 Turlington's balsam, 419 Turpentine, oil of, 85 Turpeth mineral, 653 ULMUS, 47 Uncaria, 112 Uncomocomo, 116 (note) Unguenta, 30, 40 Unguentum, 50 Upas tree, 435 Uranium, 701 Urari, 254 Urechites, 435 Urethane, 127, 191, 193 Urethra, applications to, 31 Urethra! suppositories, 40 Urginea maritima, 452 Urosin, 549 Urotropine, 76 (note), 425 Ursion, 77 Ustilago, 480 Uterus, applications to, 31 Uva ursi, 77 TTAGINA, applications to, 31 Y Vaginal suppositories, 40 Valerian, 73 Valerianates, 551 Vallet's mass, 666 Valyl, 74 Vanadium, 701 Vanilla, 67 Vanillin, 71 Vaseline, 50 Vegetable astringents, 109 cathartic pill, 105 ferments, 707 purgatives, 93 Veratrine, 334 Veratrum, 334 Verbascum, 48 Vermicides, 115 Vermifuges, 115 Verpnal, 127, 192, 193 Vesicans, collodium, 728 Vesicants, 78 Vienna paste, 570 Vina, 39 Vinegar, 563 medicated, 40 Vini gallici, spiritus, 145 752 INDEX. Vinum album, 145 aurantii, 145 rubrum, 145 xericum, 145 Vioform, 519 Violet, 340 Virginian cherry, 67, 239 prune, 67 Volatile oils, 61, 387, 426 WAHOO, 105, 452 Warburg's tincture, 364 Warming plaster, 91, 728 Wash, black, 653 yellow, 653 Washes, 39, 653 Water, 486 aerated, 580 glass, 728 hemlock, 432 potash, 580 soda, 580 Watering places, 492 Waters, iron, 667 medicated, 38 Wax, 51, 727 Weight, influence of, on dose, 25 Whiskey, 72, 145 Willow, 413 Wine, 145 Wines, medicated, 39 Wintergreen, oil of, 68, 386, 412 Witchhazel, 113 Wood alcohol, 144 Wood tar, 386 Wool fat, 50 Woorali, 254 Woorara, 254 Wormseed, American, 124 Levant, 122 Wormwood, 65, 426 Wristdrop, 673 VANTHIN, 244 A. Xanthopsia, 121 Xeroform, 695 Xylol, 385, 392 jasmine, 263 I sight, 121 wash, 653 Yerba Mate, 244 Young's formula, 25 Youpon, 244 Yttrium, 495 (note) ZEA, 77 Zinc, 624, 683 Zinc chloride, 685 haemol, 685 peroxide, 590 phenolsulphonate, 685 phosphide, 601 sozoiodolate, 519 sulphocarbolate, 417, 685 Zincum, 685 Zingiber, 67, 72